Analogues of camptothecin, their use as medicaments and the pharmaceutical compositions containing them

ABSTRACT

A method of treating a cancer in warm-blooded animals by administration to the warm-blooded animals in need thereof a camptothecin analog a 7-ring member beta-hydroxy lactone ring of the formulawherein the substituents are defined as in the specification.

This application is a divisional of Ser. No. 09/332,520, filed Jun. 14,1999, now U.S. Pat. No. 6,339,091, which is a continuation-in-part ofSer. No. 08/973,561, filed Dec. 2, 1997, now U.S. Pat. No. 5,981,542,which is a continuation-in-part of PCT/FR96/00980, filed Jun. 21, 1996,and said Ser. No. 09/332,520 is a continuation-in-part ofPCT/FR97/02217, filed Dec. 5, 1997 and a continuation-in-part ofPCT/FR97/02218, filed Dec. 5, 1997 and a continuation-in-part ofPCT/FR98/01768, filed Aug. 7, 1998.

Camptothecin is a natural compound which has been isolated for the firsttime from the leaves and the bark of the Chinese plant calledcamptotheca acuminata (see Wall et al. J. Amer. Chem. Soc. 88:3888(1966)). Camptothecin is a pentacyclic compound constituted by anindolizino[1,2-b]quinoline fragment fused with an α-hydroxylactone withsix members. The carbon in position 20 which cares the α-hydroxy groupis asymmetrical and confers a rotatory power on the molecule. Thenatural form of camptothecin has an absolute “S” configuration asregards the carbon 20 and corresponds to the following formula:

Camptothecin has an anti-proliferative activity in several cancerouscell lines, including the cell lines of human tumors of the colon, lungand breast (Suffness, M et al: The Alkaloids Chemistry and Pharmacology,Bross A., ed., Vol, 25, p. 73 (Acedemic Press, 1985)). It is suggestedthat the anti-proliferative activity of camptothecin is related to itsinhibitory activity on DNA topoisomerase I.

It has been indicated that α-hydroxylactone was an absolute requirementboth for the in vivo and in vitro activity of camptothecin(Camptothecins: New Anticancer Agents, Putmesil, M et al, ed., p. 27(CRC Press, 1995); Wall M, et al, Cancer Res. 55:753 (1995); Hertzberget al, J. Med. Chem. 32:715 (1982) and Crow et al, J. Med. Chem. 35:4160(1992)), The present invention relates to a new class of compounds ofcamptothecin, in which a β-hydroxylactone replaces the naturalα-hydroxylactone of camptothecin. The compounds according to the presentinvention present a powerful biological activity which is unexpectedwith regard to the state of the prior ant.

Therefore a subject of the invention is new analogues of camptothecinwhich differ from all known derivatives of camptothecin in the sensethat they contain β-hydroxylactone (or its open hydroxycarboxylic form)instead of an α-hydroxylactone (or its open hydroxycarboxylic form); ora pharmaceutically acceptable salt of one of the latter. By derivativeof camptothecin is meant a compound having the same structural skeletonas that of camptothecin (i.e. an indolizino[1,2-b]quinoline fragmentfused with an α-hydroxylactone with six members), with or without otherchemical substitutions on the skeletal structure. Different derivativesof camptothecin are well known by specialists, as described hereafter.By β-hydroxylactone is meant a lactone which contains an additionalcarbon atom between the carbon of the carboxyl and the α-carbon carryingthe hydroxyl group in the α-hydroxylactone.

An analogue of camptothecin according to the invention can thereforecontain substitutions on the indolizino[1,2-b]quinoline fragment (forexample in order to improve the solubility of the compound), or on theopen or closed β-hydroxylactone (for example in order to improve thestability of the compound). Examples of substitutions on the closedβ-hydroxylactone include an alkyl substitution (for example ethyl) onthe β-carbon. Examples of substitutions on the open β-hydroxylactoneinclude alkyl substitutions on the β-carbon, substitutions (for examplean amidation) on the resultant carboxylic acid and substitutions (forexample an esterification) or suppressions of the resultant hydroxylgroup.

Preferred β-hydroxylactone camptothecin analogues are notably those inwhich the pentacyclic skeletton is substituted at least once by anhalogen atom in any of positions 9,10, 11 or 12.

The invention first relates to compounds of general formula (B1) and(B2)

in racemic or enantiomeric form or any combinations of these forms, inwhich

R₁ represents a lower alkyl; a lower alkenyl, a lower alkynyl, a lowerhaloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;

R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl, loweralkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl,amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lowerazidoalkyl, (CH₂)_(m)NR₆R₇, (CH₂)_(m)OR₆, (CH₂)_(m)SR₆, (CH₂)_(m)CO₂R₆,(CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)C(O)R₈, (CH₂)_(m)OC(O)R₈, O(CH₂)_(m)NR₆R₇,OC(O)NR₆R₇, OC(O)(CH₂)_(m)CO₂R₆ or (CH₂)_(n)[N═X], OC(O)[N=X],(CH₂)_(m)OC(O)[N═X] (in which [N═X], in this invention, represents aheterocyclic group with 4 to 7 members with the nitrogen atom N, whichis a member of the heterocyclic group, and X represents the remainingmembers, which are necessary to complete the heterocylic group; selectedfrom the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀),substituted or non substituted aryl or lower arylalkyl (i.e. substitutedbetween once and four times on the aryl group or the heterocycle), inwhich the substituent is a lower alkyl, halo, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl) or R₂ and R₃ form together a chain with 3 or 4members in which the elements of the chain are selected from the groupconstituted by CH, CH₂, O, S, N or NR₉;

R₅ represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, loweralkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyllower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lowerhydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈, (CH₂)_(m)NR₆C(O)R₈,(CH₂)_(m)NR₆R₇, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR₆R₇, (CH₂)_(m)OC(O)R₈,(CH₂)_(m)OC(O)NR₆R₇, (CH₂)_(m)S(O)_(q)R₁₁, (CH₂)_(m)P(O)R₁₂R₁₃,(CH₂)₂P(S)R₁₂R₁₃ or (CH₂)_(n)[N═X], OC(O)[N═X], (CH₂)_(m)OC(O)[N═X],substituted or non substituted aryl or lower arylalkyl (i.e. substitutedbetween once and four times on the aryl or heteroaryl group), in whichthe substituent is a lower alkyl, halo, hydroxy, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl;

R₆ and R₇ represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl,or aryl or lower arylalkyl in which the aryl group is substituted by oneor more groups chosen from the following radicals: lower alkyl, halo,nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl;

R₁₀ represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl oraryl substituted (i.e. having one to four substituents on the arylgroup) by one or more groups chosen from the following radicals: loweralkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;

R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, lower alkoxy,aryloxy or

R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

R₁₆ represents H or OR₂₁;

R₁₇ represents OR₆ or NR₆R₇;

R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, lower alkoxyor hydroxy;

R₂₀ represents H or halo;

R₂₁ represents H, a lower alkyl, CHO or C(O)(CH₂)_(m)CH₃;

R_(p) represents H or an easily cleavable group preferably chosen fromthe groups corresponding to the formula —C(O)—A—NR₂₂R₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals, while R₂₂ and R₂₃, independently, represent H, alower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, loweraminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, loweralkoxy lower alkyl, lower haloalkyl, or substituted or non substitutedaryl or lower arylalkyl (i.e., substituted one to four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

m is an integer comprised between 0 and 6;

n is 1 or 2; and

q represents an integer from 0 to 2; and

[N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀:

or pharmaceutically acceptable salts of the latter.

The invention especially relates to compounds of general formula (HCPT)

in racemic or enantiomeric form or any combinations of these forms, inwhich

R₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, a lowerhaloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower

R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl, loweralkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl,amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lowerazidoalkyl, (CH₂)_(m)NR₆R₇, (CH₂)_(m)OR₆, (CH₂)_(m)SR₆, (CH₂)_(m)CO₂R₆,(CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)C(O)R₈, (CH₂)_(m)OC(O)R₈, O(CH₂)_(m)NR₆R₇,OC(O)NR₆R₇, OC(O)(CH₂)_(m)CO₂R₆ or (CH₂)_(n)[N═X], OC(O)[N═X],(CH₂)_(m)OC(O)[N═X] (in which [N═X], in this invention, represents aheterocyclic group with 4 to 7 members with the nitrogen atom N, whichis a member of the heterocyclic group, and X represents the remainingmembers, which are necessary to complete the heterocylic group, selectedfrom the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀),substituted or non substituted aryl or lower arylalkyl (i.e. substitutedbetween once and four times on the aryl group or the heterocycle), inwhich the substituent is a lower alkyl, halo, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl) or R₂ and R₃ form together a chain with 3 or 4members in which the elements of the chain are selected from the groupconstituted by CH, CH₂, O, S, N or NR₉;

R₅ represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, loweralkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyllower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lowerhydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈, (CH₂)_(m)NR₆C(O)R₈,(CH₂)_(m)NR₆R₇, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR₆R₇, (CH₂)_(m)OC(O)R₈,(CH₂)_(m)OC(O)NR₆R₇, (CH₂)_(m)S(O)_(q)R₁₁, (CH₂)_(m)P(O)R₁₂R₁₃,(CH₂)₂P(S)R₁₂R₁₃, substituted or non-substituted (CH₂)_(n)[N═X] radical,OC(O)[N═X], (CH₂)_(m)OC(O)[N═X], substituted or non substituted aryl orlower arylalkyl (i.e. substituted between once and four times on thearyl or heteroaryl group), in which the substituent is a lower alkyl,halo, hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

R₆ and R₇ represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aninoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl,or aryl or lower arylalkyl in which the aryl group is substituted by oneor more groups chosen from the following radicals: lower alkyl, halo,nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl;

R₁₀ represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl oraryl substituted (i.e. having one to four substituents on the arylgroup) by one or more groups chosen from the following radicals: loweralkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;

R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, lower alkoxy,aryloxy or amino;

R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

R₁₆ represents H or OR₂₁;

R₁₇ represents OR₆ or NR₆R₇;

R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, lower alkoxyor hydroxy;

R₂₀ represents H or halo;

R₂₁ represents H, a lower alkyl, CHO or C(O)(CH₂)_(m)CH₃;

R_(p) represents H or an easily cleavable group preferably chosen fromthe groups corresponding to the formula —C(O)—A—NR₂₂R₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals, while R₂₂ and R₂₃, independently, represent H, alower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, loweraminoalkyl, cycloalkyl, cycloalkyl lower alkyl,lower alkenyl, loweralkoxy lower alkyl, lower haloalkyl, or substituted or non substitutedaryl or lower arylalkyl (i.e., substituted one to four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

m is an integer comprised between 0 and 6;

n is 1 or 2; and

q represents an integer from 0 to 1, and

[N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S;CH₂, CH, N, NR₉ and COR₁₀;

or pharmaceutically acceptable salts of the latter.

For the compounds of general formulae (B1), (B2) and (HCPT) (and inextenso the compounds of general formulae (I) and (II)), the followingpreferences apply independently to the substituents:

R₁ represents a lower alkyl, and preferably ethyl;

R₂ represents halo;

R₃ represents halo, lower alkyl or lower haloalkyl; when R₃ is a loweralkyl, R₃ is preferably methyl or ethyl;

R₅ represents halo, lower alkyl, lower haloalkyl, lower aminoalkyl,substituted or non substituted (CH₂)_(n)[N═X] radical, substituted ornon substituted aryl or lower arylalkyl; preferred (CH₂)_(n)[N═X]radicals include lower alkyl, and piperazines, especially methylsubstituted piperazines;

R₁₈ and R₁₉ represent H.

R₂₀ represents H.

The invention particularly relates to the following compounds which aredescribed as examples of compounds responding to the general formula(B1) or the general formula (B2)

tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;

ethyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;

5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoicacid;

methyl3-hydroxy-3-[8-(methoxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

ethyl2,2-difluoro-3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;

ethyl3-hydroxy-3-(8-methyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin7-yl)pentanoate;

tert-butyl3-{8-[(acetyloxy)methyl]-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl}-3-hydroxypentanoate;

5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

3-[12-ethyl-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoicacid;

8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

3-[2-(benzyloxy)-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoicacid (E);

5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

11-[(dimethylamino)methyl]-5-ethyl-5,10dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;

9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,71indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-10fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione,

5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;,

9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,71indolizino[1,2-b]quinoline-3,15-dione;

5ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dion;

5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-(4morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[3,6-dihydro-1(2H)-pyridylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-choro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-{[benyl(methyl)amino]methyl]-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4-benzyl-1-piperazinyl)methyl]-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[3,6dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino1,2-b]quinoline-3,15dione;

5-ethyl-9-fluoro-5-hydroxy-10methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-3,15-dione;

5ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino(1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl2-aminoacetate;

5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl3-aminopropanoate;

2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

9-ethyl-9-hydroxy2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridine;

or a pharmaceutically acceptable salt of the latter.

The invention more particularly relates to the following compoundscorresponding to the formula (HCPT):

5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;.

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,5-dione;

9chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15dione;

7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;

9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3H,15-dione;

5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[3,6dihydroxy-1(2H)-pyridinylmethyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-{[benzyl(methyl)amino]methyl}-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4benzyl-1-piperazinyl)methyl]-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(dimethylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione:

12-[3,6-dihydro-1(2H)-pyridylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6.7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinolin-5-yl2-aminoacetate;

5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinolin-5-yl3-aminopropanoate;

2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

(+)-5-ethyl-9,10-difluoro-5-hydroxy4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

or pharmaceutically acceptable salts of the latter.

Among the above list of compounds, the following are preferred:

5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione,

9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5,12-diethyl-9-fluoro-5hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,151H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(dimethylamino)methyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(4benzyl-1-piperazinyl)methyl]9chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4methyl-1piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(diisobutylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-12-[(dimethylamino)methyl]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl)]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

or a pharmaceutically acceptable salt of the latter.

Among the above list of compounds, the following are more preferred:

5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

5ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione,

9-chloro-5-ethyl-5-hydroxy-10methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indoizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione,

5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

10chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

9chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[(diethylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3;15-dione;

5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indoizino[1,2-b]quinoline-11,14-dione;

2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

(+)-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

or a pharmaceutically acceptable salt of the latter.

Among the above lists of compounds, particularly preferred compounds forthe present invention are the following:

5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizilo[1,2-b]quinoline-3,15-dione

(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinollne-3,15-dione;

(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

or a pharmaceutically acceptable salt of the latter.

Among the above lists of compounds, more particularly preferredcompounds for the present invention are the following:

(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

or a pharmaceutically acceptable salt of the latter.

A more particular subject of the invention is the compounds of generalformula (I) and general formula (II),

in racemic or enantiomeric form or any combinations of these forms, inwhich

R₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, a lowerhaloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;

R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl, loweralkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl,amido, lower aminoalkyl, hydrazino, lower hydrazinoalkyl, azido, lowerazidoalkyl, (CH₂)_(m)NR₆R₇, (CH₂)_(m)OR₆, (CH₂)_(m)SR₆, (CH₂)_(m)CO₂R₆,(CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)C(O)R₈, (CH₂)_(m)OC(O)R₈, O(CH₂)_(m)NR₆R₇,OC(O)NR₆R₇, OC(O)(CH₂)_(m)CO₂R₆ or (CH₂)_(n)[N═X], OC(O)[N═X],(CH₂)_(m)OC(O)[N═X] (in which [N═X], in this invention, represents aheterocyclic group with 4 to 7 members with the nitrogen atom N, whichis a member of the heterocyclic group, and X represents the remainingmembers, which are necessary to complete the heterocylic group, selectedfrom the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀),substituted or non substituted aryl or lower arylalkyl (i.e. substitutedbetween once and four times on the aryl group or the heterocycle), inwhich the substituent is a lower alkyl, halo, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl) or R₂ and R₃ form together a chain with 3 or 4members in which the elements of the chain are selected from the groupconstituted by CH, CH₂, O, S, N or NR₉;

R₅ represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, loweralkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyllower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lowerhydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈, (CH₂)_(m)NR₆C(O)R₈,(CH₂)_(m)NR₆R₇, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR₆R₇, (CH₂)_(m)OC(O)R₈,(CH₂)_(m)OC(O)NR₆R₇, (CH₂)_(m)S(O)_(q)R₁₁, (CH₂)_(m)P(O)R₁₂R₁₃,(CH₂)₂P(S)R₁₂R₁₃ or (CH₂)_(n)[N═X], OC(O)[N═X], (CH₂)_(m)OC(O)[N═X],substituted or non substituted aryl or lower arylalkyl (i.e. substitutedbetween once and four times on the aryl or heteroaryl group), in whichthe substituent is a lower alkyl, halo, nitro, amino, lower alkylamino,lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy loweralkyl;

R₆ and R₇ represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl,or aryl or lower arylalkyl in which the aryl group is substituted by oneor more groups chosen from the following radicals: lower alkyl, halo,nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl;

R₁₀ represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl oraryl substituted (i.e. having one to four substituents on the arylgroup) by one or more groups chosen from the following radicals: loweralkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;

R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, lower alkoxy,aryloxy or amino;

R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

R₁₆ represents H or OR₂₁;

R₁₇ represents OR₆ or NR₆R₇;

R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, lower alkoxyor hydroxy;

R₂₀ represents H or halo;

R₂₁ represents H, a lower alkyl, CHO or C(O)(CH₂)_(m)CH₃;

m is an integer comprised between 0 and 6;

n is 1 or 2; and

q represents an integer from 0 to 2; and

[N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀:

or a pharmaceutically acceptable salt of the latter.

A particular subject of the invention is the compounds of formulae I andII as defined above in which R₁ represents a lower alkyl, lower alkenyl,lower haloalkyl, lower alkoxy lower alkyl or lower alkylthio loweralkyl; R₅ represents H, halo, lower haloalkyl,lower alkyl, lower alkoxy,lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl,cycloalkyl lower alkyl, cyano, cyanoalkyl, lower hydroxyalkyl, nitro,(CH₂)_(m)C(O)R₈, (CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)NR₆R₇,(CH₂)_(m)N(CH₃)(CH₂)_(n)NR₆R₇, (CH₂)_(m)OC(O)R₈, (CH₂)_(m)OC(O)NR₆R₇, or(CH₂)_(n)[N═X], OC(O)[N═X], (CH₂)_(m)OC(O)[N═X], substituted or nonsubstituted aryl or lower arylalkyl; R₁₂ and R₁₃ represent,independently, a lower alkyl; R₁₆ represents OR₂₁; and R₁₈, R₁₉ and R₂₀represent H.

The invention has more particularly as its subject matter the compoundsof formula (I) and (II) as is defined above in which R₁ represents alower alkyl, lower alkenyl, lower haloalkyl or lower alkoxy lower alkyl;R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl, loweralkyl, nitro, amido, lower aminoalkyl, hydrazino, lower hydrazinoalkyl,azido, lower azidoalkyl, (CH₂)_(m)NR₆R₇, (CH₂)_(m)OR₆, (CH₂)_(m)SR₆,(CH₂)_(m)C(O)R₈, (CH₂)_(n)[N═X], or (CH₂)_(m)OC(O)[N═X] substituted ornon substituted, or OC(O)[N═X]; or R₂ and R₃ form together a chain with3 or 4 members in which the elements of the chain are selected from thegroup constituted by CH, CH₂, O, S, N or NR₉; R₅ represents H, halo,lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl,lower alkylthio lower alkyl, lower hydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈,(CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)NR₆R₇, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR₆R₇,(CH₂)_(m)OC(O)R₈, (CH₂)_(m)OC(O)NR₆R₇, or (CH₂)_(n)[N═X], OC(O)[N═X]substituted or non substituted or (CH₂)_(m)OC(O)[N═X]; R₆ and R₇represent, independently, H, a lower alkyl, lower hydroxyalkyl, loweralkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl loweralkyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or nonsubstituted aryl or lower arylalkyl; R₈ represents H, a lower alkyl,lower hydroxyalkyl, lower alkylamino, lower alkyl lower aminoalkyl,lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl,lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substitutedor non substituted aryl or lower arylalkyl; R₉ represents H, a loweralkyl or lower haloalkyl; R₁₀ represents H, a lower alkyl, lowerhaloalkyl or lower alkoxy; R₉ represents H or lower alkyl; and R₁₄ andR₁₅ represent, independently, H or lower alkyl.

In a more preferred manner, R₂ represents H or halo and preferably H,chloro or fluoro; and R₃ represents H, a lower alkyl, halo or OR₆ inwhich R₆ represents H, a lower alkyl or a lower arylalkyl and preferablyH, fluoro, chloro, methyl or methoxy. Also in a more preferred manner,R₂ and R₃ together form a methylenedioxy or an ethylenedioxy.

A more particular subject of the invention is the compounds of formula(I) and (II) for which R₂ represents a hydrogen or, halogen atom, R₃represents a halogen atom, a lower alkyl or a lower alkoxy, R₄ and R₁₆represent hydrogen atoms, and R₁₈, R₁₉ and R₂₀ represent hydrogen atoms;or a pharmaceutically acceptable salt of the latter. An aminoalkylradical will then preferably be chosen for R₅.

A more particular subject of the invention is the products describedhereafter in the examples and corresponding to the following formulae:

5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(1,2,5,6-tetrahydopyridinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dionehydrochloride

5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9,10difluoro-4,5-dihydro-5-hydroxy-12-(methylpiperazinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9,10difluoro-4,5-dihydro-5-hydroxy-12-dimethylamino-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-morpholinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperazinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

12-benzylpiperazinomethyl-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

12-(4-benzylpiperazinomethyl)-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13h)-dione

5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-dimethylaminomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-12-dimethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9-fluoro-5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9-fluoro-4,5dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(1,2,5,6,-tetrahydropyridinomethyl)-1H-oxepino[3′4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

12-diisobutylaminomethyl-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-dimethylaminomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dionehydrochloride

5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(1,2,5,6-tetrahydropyridinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dionehydrochloride

5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-4,5-dihydro-5-hydroxy-10methoxy-12-(4-methylpiperazinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

12-(4-benzylpiperazinomethyl)-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3′,4′,6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

or a pharmaceutically acceptable salt of the latter.

A more particular subject of the invention is the compounds of formula(I) as defined above, in which R₁ represents the ethyl group; R₂ and R₃represent, independently, H, a lower alkyl, halo, lower alkyl halo or(CH₂)_(m)OR₆, or R₂ and R₃ form together a methylenedioxy or anethylenedioxy; R₄ and R₅ represent, independently, H, a lower alkyl,(CH₂)_(m)NR₆R₇, or (CH₂)_(n)[N═X] non substituted or substituted by alower alkyl; R₂₀ represents H and R₁₇ represents OR₆, in which R₆represents H or a lower alkyl, or NR₆R₇ in which R₆ and R₇,independently, represent H, a lower alkyl, aryl or lower alkyl aryl.Preferably, R₄ represents H or (CH₂)_(m)NR₆R₇, in which R₆ and R₇represent, independently; H or a lower alkyl; R₅ represents H, a loweralkyl or (CH₂)_(n)[N═X] non substituted or substituted by a lower alkyl;and R₁₇ represents OR₆ in which R₆ represents H or a lower alkyl; or apharmaceutically acceptable salt of the latter. As an example ofsubstituted or non substituted [N═X], there can be mentioned thepiperidyl, morpholinyl, piperazinyl, imidazolyl and 4-methylpiperazinylradical.

In a more preferred manner, R₂ represents H or halo and preferably H,chloro or fluoro; R₃ represents H, a lower alkyl, halo or OR₆ in whichR₆ represents H, a lower alkyl or a lower alkyl aryl and preferably H,fluoro, chloro, methyl or methoxy. Also in a more preferred manner R₂and R₃ form together dioxymethylene or dioxyethylene.

A more particular subject of the invention is the products describedhereafter in the examples, in particular the products corresponding tothe following formulae:

5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,73]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dionehydrochloride;

5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

or a pharmaceutically acceptable salt of the latter

Camptothecin and certain of its analogues are not hydrosoluble, whichmakes their administration by parenteral route difficult. Hydrosolublederivatives of camptothecin have been prepared where rings A and B carrysalifiable substituents (cf. for example U.S. Pat. Nos. 4,981,968,5,049,668, EP 540,099). However, these products revealed an antitumoralactivity which was reduced with respect to that of non-hydrosolublederivatives. Other hydrosoluble derivatives of camptothecin have alsobeen prepared where the hydroxyl group in position 20 is esterified byan acid carrying a salifiable radical such as for example glycine (cf.U.S. Pat. No. 4,943,579 and PCT No. WO 96/02546). These derivatives aredesignated by a person skilled in the art under the name “prodrug forms”as they are not biologically active in themselves, but only after afirst metabolization phase once administered to the patient. The prodrugforms of the α-hydroxylactone analogues of camptothecin have shown agood anti-tumoral effectiveness in animals and clinically, butaccompanied by damaging side-effects such as the appearance of seriousdiarrhoeas which can put the patient's life in danger. It is thereforenecessary to develop hydrosoluble analogues of camptothecin which aremore effective and better tolerated.

Hydrosolubility of the camptothecin analogues being important, somecompounds according to the present invention have also been designed inorder to possess this property as well.

Two solutions were chosen in order to increase the hydrosolubility ofthe camptothecin analogues: the first consists in grafting an oxazineonto the A ring of the molecule, and the second in designing prodrugforms by acetylating the hydroxy function of the β-hydroxylactone.

More specifically, among this new class of camptothecin analogues, thecompounds according to the present invention are either analoguesmodified by fixation of an oxazine ring on carbons 10 and 11 or prodrugforms in which a β-hydroxylactone replaces the natural α-hydroxylactoneof camptothecin. The compounds of the present invention are thereforecamptothecin analogue β-hydroxylactones on which an oxazine ring orhydrosoluble prodrugs have been grafted and present a powerfulbiological activity which is unexpected in the light of the state of theprior art.

Another object of the invention is therefore the compounds of formula(I)_(op) and formula (II)_(op):

in racemic or enantiomeric form or any combinations of these forms, inwhich

R₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, a lowerhaloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;

R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl, loweralkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl,amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lowerazidoalkyl, (CH₂)_(m)NR₆R₇, (CH₂)_(m)OR₆, (CH₂)_(m)SR₆, (CH₂)_(m)CO₂R₆,(CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)C(O)R₈, (CH₂)_(m)OC(O)R₈, O(CH₂)_(m)NR₆R₇,OC(O)NR₆R₇, OC(O)(CH₂)_(m)CO₂R₆ or (CH₂)_(n)[N═X], OC(O)[N═X],(CH₂)_(m)OC(O)[N═X] (in which [N═X], in this invention, represents aheterocyclic group with 4 to 7 members with the nitrogen atom N, whichis a member of the heterocyclic group, and X represents the remainingmembers, which are necessary to complete the heterocylic group, selectedfrom the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀), aryl orlower arylalkyl substituted (i.e. substituted between once and fourtimes on the aryl group or the heterocycle) or non substituted, in whichthe substituent is a lower alkyl, halo, nitro, amino, lower alkylamino,lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy loweralkyl or R₂ and R₃ or R₃ and R₄ form together a chain with 3 or 4members in which the elements of the chain are selected from the groupconstituted by CH, CH₂, O, S, N or NR₉;

R₅ represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, loweralkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyllower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lowerhydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈, (CH₂)_(m)NR₆C(O)R₈,(CH₂)_(m)NR₆R₇, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR₆R₇, (CH₂)_(m)OC(O)R₈,(CH₂)_(m)OC(O)NR₆R₇, (CH₂)_(m)S(O)_(q)R₁₁, (CH₂)_(m)P(O)R₁₂R₁₃(CH₂)₂P(S)R₁₂R₁₃ or (CH₂)_(n)[N═X], OC(O)[N═X], (CH₂)_(m)OC(O)[N═X],substituted or non substituted aryl or lower alkyl aryl (i.e.substituted between once and four times on the aryl or heteroarylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₆ and R₇ represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or a substituted or non substituted aryl orlower arylalkyl (i.e. substituted between once and four times on thearyl group), in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl;

R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl,or aryl or lower arylalkyl in which the aryl group is substituted by oneor more groups chosen from the following radicals: lower alkyl, halo,nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl;

R₁₀ represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl oraryl substituted (i.e. having one to four substituents on the arylgroup) by one or more groups chosen from the following radicals: loweralkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;

R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, lower alkoxy,aryloxy or amino;

R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

R₁₆ represents H or OR₂₁;

R₁₇ represents OR₆ or NR₆R₇;

R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, lower alkoxyor hydroxy;

R₂₀ represents H or halo;

R₂₁ represents H, a lower alkyl, CHO or C(O)CH₂)_(m)CH₃;

R_(p) represents H or an easily cleavable group preferably chosen fromthe groups corresponding to the formula —C(O)—A—NR₂₂R₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals, while R₂₂ and R₂₃, independently, represent H, alower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, loweraminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, loweralkoxy lower alkyl, lower haloalkyl, or substituted or non substitutedaryl or lower arylalkyl (i.e., substituted one to four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

m is an integer comprised between 0 and 6;

n is 1 or 2; and

q represents an integer from 0 to 2; and

[N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀;

it being understood that when R_(p) is a hydrogen atom, R₃ and R₄together form a chain with 3 or 4 members;

or a pharmaceutically acceptable salt of the latter.

As concerns the oxazin-grafted forms of the invention, R₂ preferablyrepresents a radical chosen from the group consisting of H, halo orlower alkyl.

As concerns the prodrug forms of the invention (those for which R_(p) isnot a hydrogen atom), the products of general formula (I)_(OP) arepreferred. Preferably, R₂ and R₃ then represent independently, a radicalchosen from the group consisting of halo or lower alkyl.

Examples of substituted camptothecins used as starting products can befound in the U.S. Pat. Nos. 4,473,692, 4,604,463, 4,894,956, 5,162,532,5,395,939, 5,315,007, 5,264,579, 5,258,516, 5,254,690, 5,212,317 and5,341,745, the PCT Patent Applications Nos. US91/08028, US94/06451,US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058 andEP95/00393 and the European Patent Application Nos. 325 247, 495 432,321 122 and 540 099.

For the compounds comprising an oxazine ring:

a β-hydroxylactonic compound of general formula D

 in which R₃ is a hydroxyl radical, R₄ is H and R₁, R₂, R₅, R₁₈, R₁₉ andR₂₀ have the meaning indicated above is treated with a primary amine,under Mannich's conditions, in order to obtain a Ehydroxylactoniccompound of general formula Ia

 in which R₁, R₂, R₅, R₉, R₁₈ R₁₉ and R₂₀ have the meaning indicatedabove.

This process consists in heating the starting product in the presence ofa primary amine such as benzylamine, of formaldehyde in an acid solventsuch as acetic acid or propionic acid at a temperature of 30° C. to 80°C. for a period of 0.5 to 5 hours. Alternatively, a suspension ofstarting product in acetic acid with a tri-N-substitutedhexahydrotriazine such as hexahydro-1,3,5-trimethyl triazine,1,3,5-triethylhexahydro triazine or 1,3,5-tribenzyl hexahydrotriazinecan be heated at a temperature of 30° C. to 80° C. for a period of 0.5to 5 hours.

the lactone of general formula Ia is opened optionally in a basic mediumin order to produce after neutralization the compound of formula IIa

 in which R₁, R₂, R₅, R₉, R₁₇, R₁₈, R₁₉ and R₂₀ have the meaningindicated above; R₁₆ represents OR₂₁ in which R₂₁ represents H or alower alkyl; and R₁₇ represents OR₆ or NHR₆ and R represents H, a loweralkyl, cycloalkyl, lower cycloalkyl alkyl, lower alkenyl, lower alkoxylower alkyl, or aryl or lower aryl alkyl.

the said compound of general formula D or Ia is optionally acylated,preferably with a derivative of the C(O)—A—N—R₂₂R₂₃ radical as definedabove in order to produce the β-hydroxylactonic compound of generalformula Ib, i.e. (I)_(op) with R_(p) different from H (prodrug form ofthe invention).

in the same manner as with the lactone Ia, the lactone Ib can be openedin order to produce hydroxyacid IIb.

The opening of the lactone ring in a basic medium can more generally beused in order to convert products of general formula (B1) in products ofgeneral formula (B2).

In the above process, the R₂, R₃, R₄ and R₅ groups can be protected ifnecessary according to standard protection methods (Greene, T.,Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)).If at least one of the R₂₂ or R₂₃ groups is H, or contains at least onefunction which is chemically incompatible with the acylation processsuch as, for example, a primary or secondary amine, it is then necessaryto use a protective group which is resistant to acylation conditions. Aprotective group commonly used for the amines is tert-butyloxycarbonyl(BOC). The acylation reaction is then carried out as described above,then the protective group is cleaved, for example by treatment withtrifluoroacetic acid in the case of BOC, in order to produce thecompound of general formula (I) or (II). Use of protective groups isknown to a person skilled in the art (for other examples, reference canbe made to Greene, T., Protective Groups in Organic Synthesis, JohnWiley & Sons, 1981).

The preparation of the compounds of general formula D is described laterin the present application.

As it is used here, the term lower with reference to the alkyl,alkylthio and alkoxy groups designates linear or branched saturatedaliphatic hydrocarbon groups containing 1 to 6 carbons, such as forexample, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio,ethylthio, methoxy and ethoxy. With reference to the alkenyl or alkynylgroups, the term lower designates groups containing 2 to 6 carbon atomsand one or more double or triple bonds, such as for example, the vinyl,allyl, isopropenyl, pentenyl, hexanyl, ethynyl propenyl, propynyl andbutynyl groups. The term cycloalkyl designates a ring with 3 to 7carbons, such as for example, the cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl groups. The term aryl designates a mono- di- or tricyclichydrocarbon compound with at least one aromatic ring, each ringcontaining a maximum of 7 members, such as for example, phenyl,naphthyl, anthracyl, biphenyl or indenyl. The term halo signifieschloro, bromo, iodo or fluoro. The radicals corresponding to theexpressions lower haloalkyl, lower cyanoalkyl, lower nitroalkyl, loweraminoalkyl, lower hydrazinoalkyl, lower azidoalkyl, lower arylalkyl,lower hydroxyalkyl, lower alkoxy lower alkyl, lower alkylthio loweralkyl, and lower alkyl lower sulphonylalkyl are substituted,respectively, by one to three halo, cyano, nitro, amido, hydrazino,azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lowersulphonylalkyl groups. The lower alkylamino radical can contain one ortwo lower alkyl groups and represent, for example, NHCH₃, NHCH₂CH₃,N(CH₃)₂ or N(CH₃)(CH₂CH₃). Examples of [N═X] include the piperidinyl,morpholinyl, piperizinyl and imidazolyl groups.

As has been observed for camptothecin, the carbon atom carrying thehydroxy function in the β-hydroxylactone or the β-hydroxycarboxylategroup of the compounds according to the present invention, isasymmetrical. Consequently, the compounds according to the presentinvention have two possible enantiomeric forms, i.e. under “R” and “S”configurations. The present invention includes the two enantiomericforms and any combinations of these forms, including “RS” racericmixtures. In an effort to simplify matters, when no specificconfiguration is indicated in the structural formulae, it should beunderstood that the two enantiomeric forms and their mixtures arerepresented.

A subject of the invention is also preparation processes for thecompounds of general formulae (B1) and (B2), either starting withcamptothecin or substituted camptothecins, or by total chemicalsynthesis.

Therefore the invention relates to a preparation process for thecompounds of formulae (B1) and (B2) according to the invention, and inparticular the products the formulae of which are indicated above,starting with camptothecin or substituted camptothecins characterized inthat:

camptothecin α-hydroxylactone of general formula

 in which R₁, R₂, R₃, R₄, R₅ and R₂₀ have the meaning indicated above,is reduced in order to obtain the α-hydroxylactol of general formula A

 in which R₁, R₂, R₃, R₄, R₅ and R₂₀ have the meaning indicated above,

in compound A thus formed, the carbon-carbon bond linking the adjacentcarbinols, is cut by treatment with an appropriate oxidizing agent so asto produce a compound of formula B

 in which R₁, R₂, R₃, R₄, R₅ and R₂₀ have the meaning indicated above,

then treatment is carried out with a functionalized alkylating agent andthe formyl function of the compound of formula B is cut in order toproduce a β-hydroxycster of general formula C

 in which R₁, R₂, R₃, R₄, R₅, R₁₈, R₁₉ and R₂₀ have the meaningindicated above, and R₁₇ represents OR₆ and R₆ represents a lower alkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl or aryl or lower aryl alkyl;

said compound of general formula C is cyclized in order to produce theβ-hydroxylactonic compound of general formula D

 in which R₁, R₂, R₃, R₄, R₅, R₁₈, R₁₉ and R₂₀ have the meaningindicated above,

the lactone of general formula D is opened in order to produce thecompound of formula E

 in which R₁, R₂, R₃, R₄, R₅, R₁₇, R₁₈, R₁₉ and R₂₀ have the meaningindicated above; R₁₆ represents OR₂₁ in which R₂₁ represents H or alower alkyl; and R₁₇ represents OR₆ or NHR₆ and R₆ represents H, a loweralkyl, cycloalkyl, cycloalkyl

Certain compounds of general formula E can also be obtained byhydrolysis of the ester function of the corresponding compounds ofgeneral formula D. The compounds of general formula E in which R₁₆and/or R₁₇ represent, independently, the hydroxy radical, can beesterified or amidified under standard conditions known to a personskilled in the art in order to obtain the corresponding esters or amidesof general formula E.

In the above process, the R₂, R₃, R₄ and R₅ groups can be protected ifnecessary according to standard protection methods (Greene, T.,Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)).During this process, the reduction is carried out using a reducing agentin an appropriate solvent, such as, for example, sodium borohydride inmethanol. The stage corresponding to the formation of compound ofgeneral formula BP starting from compound of general formula A isimplemented under oxidizing conditions, such as, for example, with leadtetraacetate, periodic acid or sodium metaperiodate in an appropriatesolvent, such as, for example, acetic acid. The treatment with afunctionalized alkylating agent can be implemented using a metallicderivative for example, of lithium or zinc, of a carboxylic ester in ananhydrous aprotic solvent such as, for example, tetrahydrofuran. Thelactonization stage which allows compound of general formula D to beobtained starting from compound of general formula C is generallycarried out under acid conditions, such as, for example, by treatmentwith trifluoroacetic acid or hydrochloric gas dissolved in an anhydroussolvent such as dichloromethane or dioxan. The opening of the lactonicring of compound of general formula D in order to obtain compound ofgeneral formula E, can be carried out, for example, by hydrolysis underalkaline conditions followed by neutralization.

Examples of substituted camptothecins used as starting products can befound in the U.S. Pat. Nos. 4,473,692, 4,604,463, 4,894,956, 5,162,532,5,395,939, 5,315,007, 5,264,579, 5,258,516, 5,254,690, 5,212,317 and5,341,745, the PCT Patent Applications Ser. Nos. US91/08028, US94/06451,US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058 andEP95/00393 and the European Patent application Nos. 325 247, 495 432,321 122 and 540 099.

Therefore, the invention also relates to a preparation process for thecompounds of formulae (B1) and (B2), characterized in that

a compound of general formula M

 in which R₁, R₁₈ and R₁₉ have the meaning indicated above and R₂₀represents a hydrogen or a halogen atom, is coupled with a2-halo-3-quinoline-methanol of general formula N

 in which R₂, R₃, R₄ and R₅ have the meaning indicated above and Xrepresents a halogen atom, in order to produce the compound of formula O

 in which R₁, R₂, R₃, R₄, R₅, R₁₈, R₁₉, R₂₀ and X have the meaningindicated above;

then the compound of general formula O is cyclized in order to obtainthe compound of general formula D as defined above.

In the above process, the R₁, R₂, R₃ and R₄ groups can be protected ifnecessary according to standard protection methods (Greene. T.,Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)).The formation of compound O starting from the compounds of generalformulae M and N is carried out with a treatment known to a personskilled in the art under the name Mitsunobu's reaction (refer toMitsunobu, O. et al. Synthesis, p.1 (1981)). The hydroxyl function ofcompound N is displaced by a nucleophile such as compound M or adeprotonated derivative of the latter, by a treatment with a phosphine,for example triphenylphosphine, and an azodicarboxylate derivative, forexample diethyl azodicarboxylate, in an aprotic solvent such as, forexample, tetrahydrofuran or N,N-dimethylformamide. The cyclization ofcompound O is preferably carried out in the presence of a palladiumcatalyst (for example palladium diacetate) under basic conditions(provided for example by an alkaline acetate optionally combined with aphase transfer agent, such as, for example, tetrabutylammonium bromide),in an aprotic solvent such as acetonitrile or N,N-dimethylformamide, ata temperature comprised between. 50° C. and 120° C. (R. Grigg et al.,Tetrahedron 46, page 4003 (1990)).

The compounds of general formula M are new. They can be preparedaccording to a process characterized in that

the carbonyl of a pyridine of general formula

 in which R₁ and R₂₀ have the meaning indicated above and R₂₂ representsa halogen atom or a lower alkoxy, is protected with an acetal function,in order to produce the compound of general formula F

 in which R₁, R₂₀ and R₂₂ have the meaning indicated above and the Z andZ′ groups represent, independently, a lower alkyl or form together asaturated hydrocarbon chain with 2to 4 carbons:

a hydroxymethyl function is introduced into the compound of generalformula F in order to obtain a compound of general formula G

 in which R₁, R₂₀, R₂₂, Z and Z′ have the meaning indicated above,

then the alcohol function of the compound of general formula G isprotected in order to produce a compound of general formula H

10 in which R₁, R₂₀, R₂₂ , Z and Z′ have the meaning indicated above andR₂₃ represents a protective group of the alcohol function.

the acetal of the compound of general formula H is deprotected in orderto produce the compound of general formula I′

 in which R₁, R₂₀, R₂₂ and R₂₃ have the meaning indicated above,

the compound of formula I′ is treated with a functionalized alkylatingagent in order to produce a β-hydroxyester of general formula J

 in which R₁, R₂₀, R₂₂ and R₂₃ have the meaning indicated above, andR₁₇, R₁₈ and R₁₉ are as defined in general formula II

the protective group R₂₃ of the compound of general formula J is cleavedin order to produce a compound of general formula K,

 in which R₁, R₁₈, R₁₉, R₂₀ and R₂₂ have the meaning indicated above,and R₁₇ represents OR₆ or NHR₆ and R₆ represents H, a lower alkyl,cycloalkyl, lower alkyl cycloalkyl, lower alkenyl, lower alkyl loweralkoxy or aryl or lower alkyl aryl,

the compound of general formula K is cyclized into the compound ofgeneral formula L

 in which R₁, R₁₈, R₁₉, R₂₀ and R₂₂ have the meaning indicated above,and finally

the R₂₂ radical of compound L is converted into carbonyl in order toobtain the compound of general formula M

 in which R₁, R₁₈, R₁₉, R₂₀, and R₂₂ have the meaning indicated above.

The carbonyl function of a 4-acyl-2-pyridine (obtained for exampleaccording to Lammattina J. L. J. Heterocyclic Chem. 20, p. 553-(1983))is preferably protected by an acetal function, preferably a cyclicacetal, according to the standard conditions known to a person skilledin the art (Greene. T., Protective Groups in Organic Synthesis 10-86(John Wiley & Sons 1981)). The intermediate thus obtained is treatedwith a sodium or potassium alcoholate in an aprotic solvent (for exampleacetonitrile), or the alcohol from which the alcoholate is derived, at atemperature comprised between 0° C. and 100° C. in order to produce thecompound of general formula F. The latter can be lithiated in position 3by treatment with an aryl- or alkyl-lithium (for examplemesityl-lithium) in an ethereal solvent such as tetrahydrofuran at atemperature comprised between −100° C. and 0° C. A formylatingelectrophile such as N,N-dimethylformamide is added to the lithiatedintermediate thus obtained, and the aldehyde thus obtained is treated,after hydrolysis, with a reducing agent such as sodium borohydride inorder to produce the compound of general formula G. The protection ofthe alcohol function of compound of general formula G is carried outaccording to the standard conditions known to a person skilled in theart, in order to obtain a compound of general formula H. Examples ofprotective groups of the alcohol function include those which formethers (i.e. methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, benzyloxymethyl, t-butyl and benzyl (substituted or nonsubstituted)), and esters (i.e. formate, acetate and isobutyrate). Forother examples of protective groups of primary hydroxyls refer toGreene. T., Protective Groups in Organic Synthesis 10-86 (John Wiley &Sons 1981). The deprotection of the compound of general formula H inorder to produce the compound of general formula I′ is carried out underselective conditions maintaining the integrity of the R₂₃ radical, forexample, by treatment under acid conditions (for example bytrifluoroacetic acid). The selective conditions for the protection anddeprotection of functional groups are known to a person skilled in theart (Greene. T., Protective Groups in Organic Synthesis 10-86 (JohnWiley & Sons 1981)). The treatment of compound of general formula I′with a functionalized alkylating agent in order to produce a β-hydroxyester of general formula J can be carried out using a lithium enolate ora zinc derivative of a carboxylic ester in an anhydrous aprotic solvent,for example, tetrahydrofuran. The protective group R₂₃ of the compoundof general formula J is cleaved in order to produce a compound ofgeneral formula K under deprotection conditions known to a personskilled in the art. For example, when R₂₃ is a benzyl group, analcoholic solution of the compound of general formula J with a palladiumcatalyst added to it can be subjected to a hydrogen atmosphere under apressure of 0.5 to 10 Bar. The cyclization of the compound of generalformula K thus obtained can be carried out under acid conditions (forexample by treatment with trifluoroacetic acid, or hydrochloric gasdissolved in an anhydrous solvent such as dichloromethane or dioxan) inorder to produce a β-hydroxylactonic ring with seven members such as inthe compound of general formula L. The compounds of general formula Lcan be converted into pyridones of general formula M, for example, bytreatment with warm hydrochloric acid, or by treatment withtrimethylsilyl iodide.

The 2-halo-3-quinoline methanols of general formula N can be obtainedstarting from the acetanilides of general formula P

in which R₂, R₃ and R₄ have the meaning indicated in the generalformulae of compounds I and II. In the processes below, the R₂, R₃ andR₄ groups can be protected if necessary according to standard protectionmethods (Greene. T., Protective Groups in Organic Synthesis 10-86 (JohnWiley & Sons 1981)).

The compounds of formula N can therefore be obtained according to thefollowing process: the said anilines of formula P are N-acetylated bytreatment with an acetylating agent such as, for example, aceticanhydride. The acetanilides thus obtained are treated at a temperaturecomprised between 50° C. and 100° C., preferably approximately 75° C.,with a reagent known to a person skilled in the art under the nameVilsmeyer's reagent (obtained by the action of phosphoryl oxychloride onNN-dimethylformamide at a temperature comprised between 0° C. and 10°C.) in order to produce the corresponding2-chloro-3-quinolinecarbaldehyde (for example, refer to Meth-Cohn et al.J. Chem. Soc., Perkin Trans. I p.1520 (1981); Meth-Cohn et al. J. Chem.Soc., Perkin Trans. I p.2509 (1981); and Nakasimhan et al. J. Am. Chem.Soc., 112 p.4431 (1990)). The chlorine in position 2 of the2-chloro-3-quinolinecarbaldehydes can be substituted by iodine orbromine by heating the product in an inert solvent such as acetonitrilein the presence of an iodine or bromine salt (for example sodium iodideor tetrabutylammonium bromide). A trace of acid such as concentratedhydrochloric acid may be necessary to catalyze this conversion. The2-halo-3-quinolinecarbaldehydes are easily reduced to the corresponding2-halo-3-quinolinemethanols of general formula N, under standardconditions known to a person skilled in the art such as treatment in analcoholic solvent (for example methanol) with sodium borohydride at atemperature comprised between 0° C. and 40° C.

The compounds of formula N can also be obtained according to thefollowing process: the anilines of general formula P as defined aboveare acylated by reaction with a nitrile (such as chloroacetonitrile orpropionitrile) in the presence of boron trichloride and another Lewisacid such as aluminium trichloride, titanium tetrachloride ordiethylaluminium chloride in an aprotic solvent or a mixture of aproticsolvents, followed by hydrolysis (cf. Sugasawa T. et al. J. Am. Chem.Soc. 100 p.4842 (1978)). The intermediate thus obtained is then treatedwith ethylmalonyl chloride in an aprotic solvent such as acetonitrile inthe presence of a base such as triethylamine, then treated with analkaline alcohol, for example, sodium methylate in methanol, in order toproduce an ethyl 2-hydroxy-3-quinolinecarboxylate substituted inposition 4. This is converted into ethyl 2-chloro-3-quinolinecarboxylateby treatment with phosphoryl oxychloride. When position 4 of thequinoline carries a chloromethyl group, a nucleophile substitution canbe carried out by treatment with a secondary amine such as, for example,dimethylamine, N-methylpiperazine, morpholine or piperidine. The ethyl2-chloro-3-quinolinecarboxylate is then reduced with diisobutylaluminiumhydride in an aprotic solvent such as dichloromethane in order toproduce the 2-chloro-3-quinolinemethanol of general formula N. Analoguesof intermediate compounds of general formula N have been described inthe literature and in particular in the PCT Application 95/05427.

The invention also offers, as a new industrial product, a compound ofgeneral formula M_(X) represented below:

wherein R is a lower alkyl group, and preferably ethyl.

This product can be used for the manufacture of medicaments.

The compound of formula M_(X) is synthesized according to a new processwhich is part of the invention and includes the following successivestages:

the racemic t-butyl ester represented below

 (for its preparation, refer in particular to the Patent Application WO97/00876) is treated with trifluoroacetic acid for 18 hours at ambienttemperate in order to produce the corresponding carboxylic acid;

then the quinidine salt of the acid obtained previously is heated inisopropyl alcohol at a temperature greater than 30° C., and preferablyat about 50° C., before leaving the reaction medium to cool down toambient temperature, so that the salt of one of the enantiomers of theabove-mentioned acid crystallized while the salt of the otherenantiomer, the anion of which is represented below, remains in solution

 the solution in isopropyl alcohol of the salt of the enantiomer whichhas not crystallized is concentrated and treated with hydrochloric acidand agitated, producing the compound of general formula A_(X)represented below

 the compound of general formula A_(X) is then put in contact withpalladium on damp carbon, then ammonium formate is added to the mixturein order to produce the debenzylated product of general formula B_(X)represented below

 then the compound of general formula B_(X) is cyclized by the action ofdicyclohexylcarbodiimide in order to obtain the lactonic compound ofgeneral formula C_(X) represented below

 finally, the —OCH₃ group of the lactonic compound of general formulaC_(X) is converted into carbonyl, by the action of sodium iodide andtrimethylsilyl chloride, in order to obtain a compound of generalformula M_(X) represented below.

For the process described above, the reaction leading from the compoundof general formula A_(X) to the compound of general formula B_(X) willpreferably take place in methanol, and preferably by heating thereaction medium to about 40° C. after the addition of the ammoniumformate. The cyclization of the compound of general formula B_(X) inorder to produce the compound C_(X) can be carried out in THF,preferably at a temperature of about 50° C., while the reaction willpreferably be carried out at ambient temperature with acetonitrile assolvent in the reaction leading from the compound of general formulaC_(X) to the compound of general formula M_(X).

In the particular case where R represents an ethyl group, the compoundof formula M_(X) is synthesized according to the process constituted bythe following successive stages:

the racemic t-butyl ester represented below

 (for its preparation, refer in particular to the Patent Application WO97/00876) is treated with trifluoroacetic acid for 18 hours at ambienttemperature in order to produce the corresponding carboxylic acid;

the quinidine salt of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid isheated in isopropyl alcohol at a temperature higher than 30° C., andpreferably at about 50° C., before leaving the reaction medium to cooldown to ambient temperature, so that the salt of the (+) enantiomer of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acidcrystallizes whilst the salt of the (−) isomer the anion of which isrepresented below, remains in solution

 the solution in isopropyl alcohol of the salt of the (−) enantiomer of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid isconcentrated and treated with hydrochloric acid and agitated, producingthe compound of formula A_(X)′ represented below

 the compound A_(X)′ is then put in contact with palladium on dampcarbon, the ammonium formate is added to the mixture in order to producethe debenzylated product B_(X)′ represented below

 then the compound of formula B_(X)′ is cyclized by the action ofdicyclohexylcarbodiimide in order to obtain the lactonic compound offormula C_(X)′ represented below

 finally, the —OCH₃ group of the lactonic compound of formula C_(X)′ isconverted into carbonyl; by the action of sodium iodide andtrimethylsilyl chloride, in order to obtain(+)-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione(or (+)-EHHOPD) represented below.

A subject of the invention is also, as new industrial products and inparticular as new industrial products intended for the preparation ofthe products of general formula (B1) and (B2); the products of generalformulae I′, M and M_(X) as described above.

Certain compounds of the invention can be prepared in the form ofpharmaceutically acceptable salts according to the usual methods.Acceptable salts include, by way of example and in a non-limitativefashion, the addition salts with inorganic acids such as hydrochloride,sulphate, phosphate, diphosphate, hydrobromide, and nitrate or withorganic acids such as acetate, maleate, fumarate, tartrate, succinate,citrate, lactate, methane sulphonate, p-toluenesulphonate, pamoate,salicylate, oxalate and stearate. The salts formed from bases such assodium or potassium hydroxide also form part of the field of applicationof the present invention, when they are useable. For other examples ofpharmaceutically acceptable salts one can refer to “PharmaceuticalSalts”, J. Pharm. Sci. 66:1 (1977).

The compounds of the present invention possess useful pharmacologicalproperties. Thus the compounds of the present invention have aninhibitory effect on topoisomerase I and/or II and an anti-tumoralactivity. The state of the art suggests that the compounds according tothe invention have an anti-parasitic and/or anti-viral activity. Thecompounds according to the present invention can also be used indifferent therapeutic applications.

An illustration of the pharmacological properties of the compoundsaccording to the invention will be found hereafter in the experimentalpart.

The compounds can inhibit topoisomerase, for example of type I and/orII, in a patient, for example a mammal such as man, by administration tothis patient of a therapeutically effective quantity of a compound offormula (B1) or a compound of formula (B2).

The compounds according to the invention also have an anti-tumoralactivity. They can be used for the treatment of tumors, for exampletumors expressing a topoisomerase, in a patient by administration to thelatter of a therapeutically effective quantity of a compound of formula(B1) or a compound of formula (B2). Examples of tumors or cancersinclude cancers of the oesophagus, the stomach, the intestines, therectum, the oral cavity, the pharynx, the larynx, the lung, the colon,the breast, the cervix uteri, the corpus endometrium, the ovaries, theprostate, the testicles, the bladder, the kidneys, the liver, thepancreas, the bone, the connective tissues, the skin, the eyes, thebrain and the central nervous system, as well as cancer of the thyroid,leukemia, Hodgkin's disease, lymphomas other than those related toHodgkin, multiple myelomas and others.

They can also be used for the treatment of parasitic infections byinhibition of the hemoflagellates (for example in trypanosomia orleishmania infections) or by inhibition of the plasmodia (such as forexample in malaria), but also the treatment of viral infections anddiseases.

These properties make the products of formula (B1) and (B2) suitable forpharmaceutical use. A subject of the present Application is also, asmedicaments, the products of formula (B1) and (B2) as defined above aswell as the addition salts with pharmaceutically acceptable mineral ororganic acids of said products of formula (B1) and (B2), as well as thepharmaceutical compositions containing at least one of the medicamentsas defined above as active ingredient.

An object of the invention is therefore methods of treatment of diseasesrelated with topoisomerase I and/or topoisomerase II disorders, andespecially cancer, viral and parasitic diseases, comprising theadministration of a therapeutically efficient dose of a camptothecinanalog, said camptothecin analog being characterized in that it featuresa β-hydroxy lactone instead of the α-hydroxy lactone of naturalcamptothecin.

Another object of the invention is methods of treatment of diseasesrelated with topoisomerase I and/or topoisomerase II disorders, andespecially cancer, viral and parasitic diseases, comprising theadministration of a therapeutically efficient dose of a compound ofgeneral formula (B1) or a compound of general formula (B2).

In particular, an object of the invention is methods of treatment aspreviously described comprising the administration of any of theβ-hydroxy lactone camptothecin analogues disclosed in the presentapplication, especially those of general formula (HCPT) and thosedescribed in the examples.

The invention also relates to pharmaceutical compositions containing acompound according to the invention or an addition salt with apharmaceutically acceptable acid of it, in combination with apharmaceutically acceptable support according to the chosenadministration method (for example oral, intravenous, intraperitoneal,intramuscular, trans-dermic or sub-cutaneous). The pharmaceuticalcomposition (for example therapeutic) can be in the form of a solid,liquid, liposome or lipidic micella.

The pharmaceutical composition can be in solid form, for example,powders, pills, granules, tablets, liposomes, gelatin capsules orsuppositories. The pill, tablet or gelatin capsule can be covered in asubstance which is capable of protecting the composition from the actionof gastric acid or enzymes in the stomach of the subject for asufficient period of time to allow this composition to pass in anon-digested form into the small intestine of the latter. The compoundcan also be administered locally, for example, at the same location asthe tumor. The compound can also be administered according to asustained release process (for example a sustained release compositionor an infusion pump). The appropriate solid supports can be, forexample, calcium phosphate, magnesium stearate, magnesium carbonate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.The pharmaceutical compositions containing a compound according to theinvention can also be presented in liquid form such as, for example,solutions, emulsions, suspensions or a sustained release formulation.The appropriate liquid supports can be, for example, water, organicsolvents such as glycerol or glycols such as polyethylene glycol,similarly their mixtures, in varied proportions, in water.

A subject of the invention is also the use of the products of formula(B1) or (B2) as defined above for the preparation of medicamentsintended to inhibit topoisomerase and more particularly topoisomerase oftype I or type II, medicaments intended for the treatment of tumors,medicaments intended for the treatment of parasitic infections, as wellas medicaments intended for the treatment of viral diseases.

Of course, the products of general formula (HCPT), (I), (II), (I)_(OP)and (II)_(OP) can be used according to the invention analogously to theproducts of formula (B1) or (B2).

The dose of a compound according to the present invention envisaged forthe treatment of the diseases or disorders mentioned above, variesaccording to the administration method, the age and body weight of thesubject as well as the state of the latter and it will be decideddefinitively by the attending doctor or vet. Such a quantity determinedby the attending doctor or vet is called here “effective therapeuticquantity”.

Unless defined in another manner, all the technical and scientific termsused here have the same meaning as that commonly understood by anordinary specialist in the field to which the invention belongs.Similarly, all publications, Patent Applications, all Patents and allother references mentioned here are incorporated by way of reference.

The following examples are presented to illustrate the above proceduresand must in no case be considered as a limit to the scope of theinvention.

EXPERIMENTAL PART EXAMPLE 1 tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

1.a.4-ethyl-3,4-dihydroxy-1,3,4,12-tetrahydro-14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-14-one

Sodium borohydride (14 g, 370 mmol) is added by portions to a suspensionof (S)-(+)-camptothecin (14 g, 40 mmol, which can be obtained fromdifferent commercial sources such as Aldrich Chemical Co. (Milwaukee,Wis.)), in methanol (750 ml) and the resultant mixture is heated gentlyto 55° C. in order to obtain a limpid solution which is then agitatedfor 16 hours at ambient temperature. The solvent is then evaporated offunder reduced pressure, the residue is taken up in water (250 ml),neutralized by the addition of acetic acid (21 ml) and left at rest for2 hours at 4° C. The resultant suspension is filtered and washedsuccessively with cold water, acetone and diethyl ether, which allowsthe sought product to be obtained, after drying under reduced pressure,in the form of a white solid m.p. 280° C.

1.b.(9-oxo-7-proplonyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate

A solution of sodium metaperiodate (14 g, 65 mmol) in water (140 ml) isadded dropwise to a suspension of4-ethyl-3,4-dihydroxy-1,3,4,12-tetrahydro-14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-14-one(13.4 g, 38 mmol) in glacial acetic acid (720 ml) and the resultantsolution is agitated for one hour at ambient temperature. The reactionmixture is then poured into an ice/water mixture (650 ml) and theresultant suspension is then agitated for half an hour then filtered andwashed successively with water, isopropyl alcohol and diethyl ether,which allows the sought product (11.5 g) to be obtained, after dryingunder reduced pressure, in the form of a pale yellow solid m.p. >200° C.(d).

1.c. tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

A suspension of zinc (6.5 g, 100 mmol) stirred with a magnetic stirrerin anhydrous diethyl ether (50 ml) under argon, is activated by thedropwise addition of chlorotrimethylsilane (0.75 ml, 5.7 mmol). Stirringis continued for 15 minutes at ambient temperature then the reactionmedium is heated to reflux. The heating bath is then removed andtert-butyl bromoacetate (15 ml, 100 mmol) is added dropwise at a ratewhich ensures reflux is maintained. The external heating is put back andheating is continued for one hour. The resultant ethereal solution ofReformatsky's reagent is left to cool down to ambient temperature thentransferred using a cannula into a suspension of(9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate (1.6 g, 4.7 mmol) in anhydrous tetrahydrofuran (40 ml) underargon. The reaction mixture is agitated under reflux for one hour, thenleft to cool down to ambient temperature and the reaction is stopped bythe addition of saturated ammonium chloride (100 ml) and extraction iscarried out with chloroform (3×100 ml). The combined chloroformicextracts are dried over sodium sulphate, evaporated and the residue ispurified by chromatography on a silica gel column (1-2% MeOH/CH₂Cl₂),which allows 0.64 g (31%) of sought product to be obtained in the formof a pale yellow solid, m.p. 146-149° C.

NMR-1H (CDCl₃): 0.93 (t, 3H); 1.37 (s, 9H); 1.99 (m, 2H); 2.97 (dd, 2H);3.5 (se, 1H); 5.10 (s, 2H); 5.24 (s, 2H); 7.40 (s, 1H); 7.59 (t, 1H);7.83 (t, 1H); 7.90 (d, 1H); 8.20 (d, 1H); 8.34 (s, 1H).

NMR-C13 (CDCl₃): 8.18; 27.90; 34.59; 45.34; 49.91; 58.55; 77.39; 82.42;100.52; 127.67; 127.97; 128.10; 128.64; 129.44; 129.79; 130.42; 130.99;142.86; 148.69; 152.75; 155.16; 162.38; 172.24.

IR (KBr): 764; 1016; 1157; 1580; 151; 1726.

EXAMPLE 2 Ethyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

A suspension of zinc (500 mg, 7.64 mmol) and(9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate (400 mg, 1.15 mmol) in anhydrous tetrahydrofuran (20 ml)containing 10 mg of hydroquinone is heated to reflux under argon. Theheating bath is removed and the exothermic reaction is initiated by theaddition of a drop of ethyl bromoacetate and a small crystal of iodine.Reflux is maintained by the dropwise addition of ethyl bromoacetate (500μl, 4.48 mmol) then the reaction mixture is again heated to reflux forone hour. After cooling down to ambient temperature, the reaction isstopped by the addition of saturated ammonium chloride (10 ml) andmethanol (30 ml). The resultant mixture is agitated for 5 minutes thenfiltered and evaporated. The residue is dissolved in dichloromethane (30ml), washed with water and dried over sodium sulphate. Then the solventis eliminated and purification using column chromatography is carriedout (SiO₂, CH₂Cl₂/MeOH 98/2), which produces 230 mg (49%) of soughtcompound in the form of a yellow solid, m.p. 157-161° C.

NMR-¹H (CDCl₃): 0.93 (t, 3H); 1.20 (t, 3H); 2.02 (m, 2H); 3.07 (dd, 2H);4.11 (q, 2H); 4.9 (se, 1H); 5.08 (s, 2H); 5.23 (s, 2H); 7.45 (s,1H);7.62 (t, 1H); 7.80 (t,1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.36 (s,1H).

NMR-C¹³ (CDCl₃): 8.09; 14.01; 34.67; 44.85; 49.94; 58.31; 61.09; 77.21;100.78; 127.78; 127.96; 128.11; 128.72; 129.16; 129.65; 130.60; 131.32;142.76; 148.28; 152.55; 155.09; 162.22; 172.59.

IR (KBr): 766; 1009; 1184; 1582; 1647; 1750.

EXAMPLE 35-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate(1.45 g, 3.32 mmol) is dissolved in anhydrous dichloromethane (25 ml)and treated with a saturated solution of hydrogen chloride indichloromethane (100 ml). The resultant mixture is maintained at −20° C.for 16 hours. The precipitate is filtered, washed with methanol anddried under reduced pressure, which allows 662 mg (55%) of soughtproduct to be obtained in the form of a yellow solid, m.p. >300° C.

NMR-¹H (DMSO): 0.90 (t, 3H); 1.20 (q, 2H); 3.27 (dd, 2H); 5.29 (s, 2H);5.49 (dd, 2H); 7.42 (s, 1H); 7.73 (t, 1H); 7.90 (t, 1H); 8.16 (t, 2H);8.71 (s, 1H).

NMR-C¹³ (DMSO): 8.45; 36.48; 42.54; 50.68; 61.44; 73.34; 99.78; 122.71;127.83; 128.15; 128.75; 129.08; 130.07; 130.61; 131.81; 144.66; 148.04;152.80; 155.91; 159.26; 172,08.

IR (KBr): 761; 1127; 1204; 1285; 1580; 1653; 1757.

EXAMPLE 43-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoicacid

An aqueous solution of potassium hydroxide (0.1N, 30 ml) is added5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(500 mg, 1.38 mmol) and the resultant suspension is agitated at ambienttemperature for 16 hours, which produces a virtually limpid solutionwhich is filtered. The filtrate is acidified to pH 3.5 with 1Nhydrochloric acid, and the yellow precipitate is recovered byfiltration, washed with water and with acetone then dried under reducedpressure. 415 mg (79%) of sought compound is obtained in the form of amonohydrate, m.p. 165-167° C.

NMR-¹H (DMSO): 0.82 (t, 3H); 2.10 (m, 2H); 2.83 (d, 2H); 3.12 (d, 2H);3.25 (se, 1H); 4.81 (s, 2H); 5.26 (s, 2H); 5.76 (se, 1H); 7.38 (s, 1H);7.71 (t, 1H); 7.84 (t, 1H); 8.10 (d, 1H); 8.18 (d, 1H); 8.34 (s, 1H);12.15 (se, 1H).

NMR-C¹³ (DMSO): 8.16; 34.80; 46.71; 50.36; 55.73; 76.53; 100.17; 127.50;128.00; 128.26; 128.69; 129.06; 130.01; 130.45; 131.63; 142.57; 148.09;153.19; 156.07; 161.22; 172.27.

IR(KBr): 1020; 1188; 1413; 1586; 1651; 1694.

EXAMPLE 5 methyl3-hydroxy-3-[8-(methoxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(180 mg, 0.5 mmol), in suspension in methanol (50 ml) is treated with 6Ndry hydrogen chloride in methanol (0.5 ml) and maintained under refluxuntil complete dissolution (4 hours). The volatile compounds areevaporated off and the residue is dissolved in dichloromethane (50 ml),washed with dilute sodium hydroxide (0.05 N, 15 ml) and brine (15 ml).The organic fraction is dried over sodium sulphate and evaporated. Thesolid residue is purified by chromatography in a silica gel column (MeOHat 3%/CH₂Cl₂) and the purified product is taken up in diethyl ether,filtered and dried, which produces 120 mg (58%) of sought compound inthe form of a pale yellow solid, m.p. 163-166° C.

NMR-¹H (CDCl₃): 0.93 (t, 3H); 1.2 (m, 2H); 3.05 (dd, 2H); 3.49 (s, 3H);3.62 (s, 3H); 4.93 (s, 2H); 5.22 (d, 2H); 5.52 (s, 1H); 7.21 (s, 1H);7.62 (t, 1H); 7.81 (t, 1H); 7.91 (d, 1H); 8.22 (d, 1H); 8.36 (s, 1H).

NMR-C¹³ (CDCl₃): 7.74; 35,54; 46.82; 50.15; 51.67; 58.10; 65.33; 78.03;100.17; 125.57; 127.70; 128.04; 128.10; 128.35; 129.53; 130.39; 130.94;143.87; 148.75; 152.94; 157.83; 161.74; 171.35.

IR (KBr): 1207; 1595; 2655; 1709.

EXAMPLE 6 ethyl2,2-difluoro-3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

Approximately half of a total quantity of ethyl bromodifluoroacetate(1.8 ml, 14 mmol),(9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate (2.0 g, 5.75 mmol, as obtained in Stage 1.b.) in suspension inanhydrous THF (10 ml), are added dropwise under argon to a suspension ofzinc (1.25 g, 17.2 mmol) in anhydrous THF under reflux (40 ml) then theremaining part of the ethyl bromodifluoroacetate is added. The reactionmixture is maintained under reflux for another half an hour. Aftercooling down to ambient temperature, the reaction is stopped by theaddition of saturated ammonium chloride (20 ml) and the reaction mixtureis extracted with dichloromethane (3×20 ml). The combined organicextracts are dried and concentrated. The residue is taken up in diethylether (10 ml), filtered and purified by column chromatography (SiO₂,CH₂Cl₂/MeOH:98/2), which produces 664 mg (26%) of product in the form ofa yellow solid, m.p. 208-209° C.

NMR-¹H (CDCl₃): 0.91 (t, 3H); 1.38 (t, 3H); 2.32 (m, 2H); 4.8 (se, 1H);4.38 (q, 2H); 5.09 (d, 2H); 5.13 (dd, 2H); 7.42 (s,1H); 7.55 (t, 1H);7.72 (t, 1H); 7.79 (d, 1H); 8.08 (d, 1H); 8.22 (s, 1H)

NMR-C¹³ (CDCl₃): 6.97; 13.93; 28.63; 50.18; 56.27; 63.15; 77.20; 81.96(t); 101.27; 116.40 (t); 127.67; 127.77; 127.97; 128.31; 129.26; 130.33;130.94; 131.23; 143.16; 148.34; 150.20; 151.91; 161.21; 163.21 (t).

IR(KBr): 1124; 1308; 1591; 1647; 1748.

EXAMPLE 7 ethyl3-hydroxy-3-(8-methyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl)pentanoate

A suspension of zinc (1.25 g, 19.1 mmol); 8-methyl-7-propionylindolizino[1,2-b]quinoline-9-(11H)-one (500 mg, 1.43 mmol, as obtained byKingsburry, W. D., Tetrahedron Lett. 29:6847 (1988)) and silver acetate(250 mg, 1.50 mmol) in anhydrous tetrahydrofuran (10 ml) is agitated atambient temperature under an argon atmosphere. After 10 minutes, thereaction mixture is activated by the dropwise addition of a molarsolution of chlorodiethylaluminium (10 ml, 10 mmol), then ethylbromoacetate (1.25 ml, 11.3 mmol) is added dropwise and the resultantmixture is left to react for another 5 hours. The reaction is stopped bythe successive addition of ethyl alcohol (10 ml) and a saturatedsolution of potassium and sodium tartrate (10 ml). The resultant mixtureis agitated for another hour, filtered and concentrated under reducedpressure. The residue is taken up in dichloromethane (30 ml). washedwith water, dried, concentrated and purified by column chromatography(SiO₂, CH₂Cl₂/MeOH:98/2), which produces 93 mg (15%) of desired productin the form of a pale yellow solid, m.p. 185-188° C.

NMR-¹H (CDCl₃): 0.91 (t, 3H); 1.17 (t, 3H); 1.99 (m, 2H); 2.49 (s, 3H);3.10 (dd, 2H); 4.11 (q, 2H); 4.6 (se, 1H); 5.25 (s, 2H); 7.65 (t, 1H);7.67 (s,1H); 7.80 (t, 1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.34 (s, 1H).

NMR-C¹³ (CDCl₃): 8.02; 13.99; 14.72; 33.14; 43.97; 50.02; 61.0; 76.54;101.90; 127.65; 127.84; 128.08; 128.81; 128.88; 130.74; 131.59; 131.65;140.33; 147.64; 152.96; 153.61; 162.11; 172.91.

IR (KBr): 762; 1192; 1576; 1653; 1740.

EXAMPLE 8 tert-butyl3-{8-[(acetyloxy)methyl]-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl}-3-hydroxypentanoate

Acetic anhydride (70 μl, 0.7 mmol) is added dropwise to a solution oftert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate(200 mg, 0.46 mmol) and triethylamine (140 μl, 1 mmol) indichloromethane (5 ml) and the resultant mixture is agitated at ambienttemperature for 21 hours. The volatile components are evaporated off andthe residue is purified by chromatography on a silica gel column (1-2%MeOH/CH₂Cl₂), which produces 152 mg of sought compound in the form of ayellow solid, m.p. 195-196° C.

NMR-¹H (CDCl₃): 0.88 (t, 3H); 1.32 (s, 9H); 1.93 (m, 2H); 2.07 (s, 3H);2.97 (dd, 2H); 4.8 (se, 1H); 5.28 (s, 2H); 5.59 (dd, 2H); 7.39 (s, 1H);7.63 (t, 1H); 7.80 (t, 1H); 7.90 (d, 1H); 8.23 (d, 1H); 8.34 (s, 1H).

NMR-C¹³ (CDCl₃): 8.02; 21.06; 27.91; 35.05; 45.58; 50.16; 59.23; 77.52;82.26; 100.59; 124.21; 127.91; 128.10; 128.14; 128.97; 129.18; 130.68;131.46; 142.85; 148.29; 152.43; 158.49; 161.83; 171.13; 171.90.

EXAMPLE 95,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is prepared in a similar manner to Example 1, except thatin Stage 1.a., 7-ethyl camptothecin (Sawada and collaborators, Chem.Pharm. Bull. 39:2574 (1991)) is used instead of camptothecin. The soughtcompound is obtained in the form of a vivid yellow solid, m.p. >270° C.

NMR-¹H (DMSO): 0.92 (t, 3H); 1.39 (t, 3H); 1.93 (q, 2H); 3.08 (d, 2H);3.25 (q, 2H); 3.51 (d, 2H); 5.32 (s, 2H); 5.52 (dd, 2H); 7.42 (s, 1H);7.76 (t, 1H); 7.89 (t, 1H); 8.18 (d, 1H); 8.32 (d, 1H).

NMR-C¹³ (DMSO): 8.46; 14.15; 22.42; 36.50; 42.54; 49.95; 61.45; 73.35;99.68; 122.61; 124.27; 126.76; 127.70; 128.27; 129.92; 130.18; 145.17;145.82; 148.57,; 152.15; 155.89; 159.26; 172.08.

EXAMPLE 103-[12-ethyl-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoicacid

This compound is prepared in a similar manner to Example 4,5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneis used instead of the5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione.It is presented in the form of a slightly dirty white solid, m.p.238-239° C.

NMR-¹H (DMSO): 0.82 (t, 3H); 1.35 (t, 3H); 2.01 (m, 2H); 2.85 (d, 2H);3.18 (d, 2H); 3.22 (q, 2H); 4.81 (s, 2H); 5.00 (se, 1H); 5.24 (s, 2H);5.78 (se, 1H); 7.38 (s, 1H); 7.77 (t, 1H); 7.86 (t, 1H); 8.18 (d, 1H);8.28 (d, 1H); 12.10 (se, 1H).

NMR-C¹³ (DMSO): 8.12; 14.15; 22.41; 34.78; 46.74; 49.65; 55.71; 76.51;100.04; 124.22; 126.63; 127.48; 128.12; 128.21; 129.94; 130.02, 143.10;145.59; 148.69; 152.62; 156.03; 161.22; 172.22.

EXAMPLE 118-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione

11.a. 4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine (F)

The water is distilled in an azeotropic manner (overnight) with a DeanStark apparatus from a mixture of 2-chloro-4-propionylpyridine (10 g, 59mmol) obtained as in Lamattina, J. L. J.Heterocyclic Chem. 20, p.553-(1983), ethylene glycol (20 ml) and p-toluenesulphonic acid (250 mg)in toluene (150 ml). The solvent is then eliminated under reducedpressure, the acid is neutralized with saturated aqueous sodiumbicarbonate (100 ml) and the product is extracted with ether. Thecombined ethereal extracts are washed with brine, dried over sodiumsulphate and evaporated, which produces 13.3 g (96%) of crude productprotected by the carbonyl group which is heated to reflux with 3equivalents of sodium methoxide in acetonitrile until the end of thereaction (checked by thin layer chromatography: SiO₂, tert-butyl methyloxide/hexane (TBMO/HX) 50/50). The acetonitrile solution is thenfiltered and evaporated. The residue is taken up in ether, washed withwater and with brine, dried over sodium sulphate and evaporated, whichproduces a brown oil which is distilled (70-75° C., 0.04 mbar); 10.7 g(overall yield 81%) of product (F) is collected in the form of a clearoil.

11.b. [4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methanol (G)

tert-butyllithium (1.7 M in pentane, 100 ml, 170 mmol) is added dropwiseusing a cannula to a solution of bromomesitylene (13 ml, 85 mmol) inanhydrous tetrahydrofuran (300 ml) at −78° C. and under argon. Theresultant white precipitate is agitated at −78° C. for one hour then4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine (10 g, 44.8 mmol) isadded and the reaction mixture is agitated for 15 minutes at −78° C. forone hour at 0° C. and for one hour at ambient temperature. After againcooling down to −78° C., anhydrous N,N-dimethylformamide (100 mmol) isadded and the reaction mixture is left to heat up to ambient temperaturethen agitated for 16 hours, after which analysis by thin layerchromatography (SiO₂, TBMO/HX: 50/50) reveals the complete consumptionof the starting product. The reaction is stopped with saturated ammoniumchloride and the reaction mixture is extracted with diethyl ether (200ml, 50 ml, 50 ml). The combined extracts are dried over sodium sulphateand evaporated, which produces a yellow oil which is purified by columnchromatography (SiO₂, TBMO/HX: 0/100 to 5/95 to elute the mestylenederivatives then 20/80 to 50/50 to elute the product) in order to obtainthe intermediate aldehyde (7 g). The aldehyde is dissolved in methanol(100 ml) and treated with sodium borohydride (5 g, 132 mmol) and theresultant mixture is agitated until complete consumption of theintermediate aldehyde (approximately 1 hour) with analytical control bythin layer chromatography. The solvent is then evaporated off, theresidue is taken up in ether, washed with water and with brine, driedand the solvent is evaporated off. Column chromatography (SiO₂, TBMO/HX:10/90 to 50/50) of the residue produces 7 g (overall yield 62%) ofproduct (G) in the form of a yellow oil.

11.c.3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine(H)

A solution of[4(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methanol (7 g, 30mmol) and benzyl chloride (5 ml, 45 mmol) in anhydrous tetrahydrofuran(50 ml) is added dropwise to a suspension of sodium hydride (80% inmineral oil, 1.85 g, 61 mmol) in anhydrous tetrahydrofuran (100 ml) andthe reaction mixture is maintained under reflux for 16 hours. Thereaction mixture is then left to cool down to ambient temperature, thereaction is stopped with water (50 ml) and the reaction mixture isconcentrated under reduced pressure. The residue is dissolved in diethylether (150 ml) and washed with water and with brine, dried andevaporated. Purification by column chromatography (SiO₂, TBMO/HX: 5/95to 20/80) produces the product protected by the benzyl (H), 9 g, (87%)in the form of a limpid oil.

11.d. 1-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-1-propanone (I′)

3-[(Benzyloxy)methyl]-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine (9g, 27 mmol) is treated with trifluoroacetic acid (10 ml) and water (5ml) at a bath temperature of 120° C. for 3 hours. The reaction mixtureis concentrated under reduced pressure and the residual traces of acidsare neutralized by the addition of saturated aqueous sodium bicarbonate.Extraction is carried out with ether followed by column chromatography(SiC₂, TBMO/HX: 10/90) which produces 5.5 g (70%) of product (I).

11.e. tert-butyl3-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-3-hydroxypentanoate (J)

tert-butyl bromoacetate (13 ml, 80 mmol) is added dropwise to a zincsuspension (5.3 g, 80 mmol activated with 6N HCl over 10 seconds, thenwashed successively with water until a neutral pH is achieved, withacetone and with diethyl ether) in anhydrous tetrahydrofuran (60 ml)under reflux. The reaction medium is maintained under reflux for another10 minutes after the addition is terminated. Then, a solution of1-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-1-propanone (5.8 g, 20mmol) in anhydrous tetrahydrofuran (20 ml) is added and the reactionmixture is agitated under reflux for another hour. The reaction isstopped at 0° C. with saturated aqueous ammonium chloride (100 ml) andthe reaction mixture is extracted with diethyl ether. The combinedextracts are dried over sodium sulphate and evaporated, which produces ayellow oil which is purified by column chromatography (SiO₂, TBMO/HX:5/95 to 10/90) in order to obtain the tert-butyl ester (J) (7 g, 95%) inthe form of a limpid liquid.

11.f. tert-butyl3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate (K)

tert-Butyl3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate (1g, 2.5 mmol) is subjected to hydrogenolysis at atmospheric pressure andat ambient temperature using 5% palladium on carbon as catalyst (50 mg)and absolute ethanol as solvent (10 ml). Once the reaction hasterminated (6 hours), the catalyst is separated by filtration and thesolvent is evaporated off, which leaves 0.7 g (90%) of product (K) of asufficient purity for a subsequent synthetic use.

11.g.5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one(L)

tert-butyl3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate (8.8 g,28 mmol) is treated with trifluoroacetic acid (30 ml) for 3 hours atambient temperature. The volatile components are evaporated off and theresidue is purified by column chromatography (SiO₂, CH₂Cl₂/MeOH: 100/0to 98/2), which produces a limpid oil which, after treatment withtoluene, produces 5.9 g of product (L) (89%) in the form of whitecrystals, m.p. 97-98° C.

11.h.5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione (M)

5-Ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one(0.5 g, 2.1 mmol) is heated under reflux for 9 hours in 1N hydrochloricacid (20 ml). The reaction mixture is concentrated under reducedpressure and the residue is again dried by the addition and evaporationof toluene twice, then left overnight under reduced pressure in thepresence of phosphorus pentoxide. The resultant oil is dissolved inanhydrous acetonitrile (5 ml) and agitated under argon for 24 hours. Theprecipitate is filtered out and dried, which produces 0.23 g (49%) of awhite solid (M), m.p. 118-119° C.

11.i. (7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methanol (N)

The procedures described by Meth-Cohn et al., J. Chem. Soc. PerkinTrans. I, p. 1520 (1981); Meth-Cohn, J. Chem. Soc. Perkin Trans. I, p.2509 (1981); and Nakasimhan et al J. Am. Chem. Soc. 112, p. 4431 (1990),are used. N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide (22 g, 113 mmol)is added to the Vilsmeyer reagent obtained by the dropwise addition ofphosphoryl oxychloride (71 ml, 0.77 mol) to anhydrous dimethylformamide(23 ml, 0.28 mol), cooled down with a water/ice bath and agitated againfor 0.5 hours under an argon atmosphere. The resultant mixture is heatedat 75° C. for 16 hours. After cooling down to ambient temperature, thereaction mixture is added to a mixture of ice and water (300 ml) andextracted with dichloromethane (5×200 ml). The combined organic extractsare dried over sodium sulphate, filtered and concentrated. The solidresidue is suspended in dichloromethane (20 ml), filtered and driedunder reduced pressure, which produces 10 g (35%) of7-chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehyde in theform of a yellow solid, m.p. 222-224° C. This intermediate is treatedwith sodium iodide (30 g, 0.2 mol) and concentrated hydrochloric acid(1.5 ml) in acetonitrile under reflux (150 ml) for 24 hours. Aftercooling down to ambient temperature, the solvent is eliminated underreduced pressure and the residue is taken up in aqueous tetrahydrofuranat 50% (200 ml), filtered, washed with tetrahydrofuran and dried underreduced pressure, which produces 12 g of7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehyde in theform of a yellow solid, m p. 155-157° C. The above intermediate istreated with sodium borohydride (2 g, 52 mmol) in methanol (200 ml) atambient temperature for 0.5 hours. The solvent is eliminated underreduced pressure and the residue is taken up in water and filtered. Theresultant solid is dried under reduced pressure in the presence ofphosphorus pentoxide, which produces 11 g of(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methanol in the formof a yellow solid, m.p. 178-180° C.

11.j.5-ethyl-5-hydroxy-8-[(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione(O)

Diethyl azodicarboxylate (570 l, 3.6 mmol) is added dropwise over 5minutes to a solution of5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione(400 mg, 1.79 mmol), the compound obtained in the preceding Stage, 11.i.(770 mg, 2.23 mmol) and triphenylphosphine (934 mg, 3.58 mmol) in amixture of anhydrous THF/DMSO (8/1 v/v, 45 ml) and the resultant mixtureis agitated under argon at ambient temperature for 16 hours. Thereaction mixture is then concentrated under reduced pressure and theresidue is dissolved in chloroform (100 ml). The resultant solution iswashed with brine (4×50 ml), dried over sodium sulphate and evaporated.The residue is purified by column chromatography (SiO₂, CH₂Cl₂/MeOH:99/1 to 98/2), which produces 650 mg (66%) of product (O) in the form ofa white solid, m.p. 165-1670° C.,

11.k.8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione

5ethyl-5-hydroxy-8-[(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione(600 mg, 1.1 mmol), tetrabutyl-ammonium bromide (352 mg, 1.1 mmol),sodium acetate (359 mg, 4.4 mmol) and palladium II acetate (98 mg, 0.43mmol) are dissolved in anhydrous acetonitrile (40 ml) and heated at 90°C. under argon for 16 hours. After cooling down to ambient temperature,a white precipitate is separated from the reddish solution. Thisprecipitate is filtered out and dried under reduced pressure. The crudeproduct is suspended in water, filtered and dried under reduced pressureover phosphorus pentoxide which produces 250 mg of sought compound inthe form of a clear yellow solid, m.p. >250° C.

NMR-¹H (DMSO): 0.91 (t, 3H); 1.87 (m, 2H); 3.08 (d, 1H); 3.51 (d, 1H);4.45 (s, 4H) 5.19 (s, 2H); 5.47 (dd, 2H); 6.02 (se, 1H); 7.33 (s, 1H);7.54 (s,1H); 7.55 (s, 1H); 8.43 (s, 1H).

NMR-C¹³ (DMSO): 8.43; 36.47; 42.54; 50.52; 61.43; 64.43-(2C); 73.31;99.07; 112.27; 113.14; 122.00; 124.24; 128.18; 129.74; 144.59; 145.01;145.33; 147.63; 150.88; 155.88; 159.23; 172.07.

EXAMPLE 1210-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

12.a. [6-(benzyloxy)-2-iodo-3-quinolinyl]methanol

This compound is prepared in a similar manner to that indicated in Stage11.i. of Example 11, but by using 4 N-[4-(benzyloxy)phenyl]acetamideinstead of N-(2,3-dihydro-1,4benzodioxin-6-yl)acetamide. Purification bychromatography on a silica gel column and the use of dichloromethane aseluant are necessary in order to isolate the intermediate6-benzyloxy)-2-chloro-3-quinolinecarbaldehyde, m.p. 180-182° C. (yield8%) with sufficient purity. Then, the halogen exchange produces6-(benzyloxy)-2-iodo-3-quinolinecarbaldehyde, m.p. 155-157° C. and asubsequent reduction with sodium borohydride produces[6-(benzyloxy)-2-iodo-3-quinolinyl]methanol, m.p. 147-149° C.

12.b.8-{[6-(benzyloxy)-2-iodo-3-quinolinyl]methyl}-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione

This compound is prepared in a similar manner to that indicated in Stage11.j. of Example 11, but by using[6-(benzyloxy)-2-iodo-3-quinolinyl]methanol instead of(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methanol. Thiscompound is presented in the form of a white solid m.p. 197-199° C.

12.c.10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is prepared in a similar manner to that indicated in Stage11.k. of Example 11, but by using8-{[6-(benzyloxy)-2-iodo-3-quinolinyl]methyl}-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dioneinstead of5-ethyl-5-hydroxy-8-[(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione.The sought compound is presented in the form of a clear yellow solidm.p. >250° C.

NMR-¹H (DMSO): 0.90 (t, 3H); 1.85 (m, 2H); 3.08 (d, 1H); 3.50 (d, 1H);5.25 (s, 2H); 5.30 (s, 2H); 5.50 (dd, 2H); 6.05 (s, 1H); 7.30-7.70 (m,8H); 8.10 (d, 1H); 8.55 (s, 1H).

NMR-C¹³ (DMSO): 8.43; 36.48; 38.28; 50.65; 61.42; 70.00; 73.32; 99.05;107.71; 122.05; 123.42; 128.18; 128.26; 128.70; 129.40; 130.19; 130.48;130.63; 136.65; 144.18; 144.90; 150.53; 155.91; 157.31; 159.24; 172.06.

EXAMPLE 133-[2-(benzyloxy)-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoic acid (E)

This compound is prepared in a similar manner to that indicated inExample 4, but by using10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione instead of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione.It is presented in the form of a yellow solid, m.p. 171-173° C.

NMR-¹H (DMSO): 0.80 (t, 3H); 2.00 (m, 2H); 2.85 (d, 1H); 3.15 (d, 1H);4.80 (s, 2H); 5.25 (s, 2H); 5.30 (s, 2H); 5.75 (se, 1H); 7.30 (s, 1H);7.35-7.70 (m, 7H); 8.10 (d, 1H); 8.55 (s, 1H).

NMR-C¹³ (DMSO): 8.11; 34.75; 46.68; 50.35; 55.70; 69.97; 76.51; 99.45;107.78; 123.28; 127.64; 128.18 (2C); 128.26; 128.70 (2C); 129.33;130.17; 130.47; 130.57; 136.69; 142.79; 144.17; 150.93; 156.03; 157.19;161.20.

EXAMPLE 14 5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(370 mg, 0.79 mmol) is treated with hydrogen under atmospheric pressureand at ambient temperature using 10% palladium on carbon as catalyst (60mg) and trifluoroacetic acid as solvent (15 ml). Once the reaction isterminated (16 hours), dichloromethane (50 ml) and methanol (50 ml) areadded to the reaction mixture, the catalyst is filtered out and thevolatile components are evaporated off under reduced pressure whichallows the sought crude compound to be obtained containing traces oftrifluoroacetic acid. These traces are eliminated by co-distillationwith 1,4-dioxan. The product is obtained in the form of an orange solid,m.p. 150° C. (d), of a sufficient purity for a subsequent synthetic use.

NMR-¹H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.02 (d, 1H); 3.45 (d, 1H);5.19 (s, 2H); 5.37 (d, 1H); 5.50 (d, 1H), 5.98 (se, 1H); 7.26 (s,1H);7.31 (s, 1H); 7.40 (d, 1H); 8.00 (d, 1H); 8.42 (s, 1H); 10.32 (s, 1H).

NMR-C¹³ (DMSO): 8.47; 36.50; 42.61; 50.57; 61.46; 73.35; 98.84; 109.02;121.83; 123.18; 129.50; 129.85; 130.12; 130.80; 143.39; 145.10; 149.69;155.97; 156.82; 159.30; 172.11.

EXAMPLE 1511-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

15.a.11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (260 mg, 0.69 mmol) inacetic acid (15 ml) is treated with aqueous formaldehyde at 37% (500 μl)and aqueous dimethylamine at 40% (500 μl) and the resultant mixture isagitated at ambient temperature for 16 hours. The reaction mixture isconcentrated to dryness and the residue is purified by columnchromatography (SiO₂, CH₂Cl₂/MeOH: 100/0 to 90/10) followed bycrystallization from acetonitrile, which produces 102 mg of soughtcompound.

15.b.11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

Dilute hydrochloric acid (1N) is added dropwise to a suspension of11-(dimethylamino) methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15 (4H,13H)-dione (102 mg) inwater until complete dissolution. The water is evaporated off underreduced pressure and the residue is suspended in acetonitrile (5 ml) andfiltered, which produces 103 mg of the sought salt m.p. 248° C. (d).

NMR-¹H (DMSO): 0.88 (t, 3H); 1.85 (m, 2H); 2.84 (s, 6H); 3.08 (d, 1H);3.5 (d, 1H); 4.73 (s, 2H); 5.25 (s, 2H); 5.47 (dd, 2H); 7.33 (s, 1H);7.38 (s,1H); 7.72 (d, 1H); 8.19 (d, 1H); 8.99 (s, 1H); 9.92 (se, 1H);11.45 (s, 1H).

NMR-C¹³ (DMSO): 8.46; 34.36; 42.44 (3C); 50.61 (2C); 61.42; 73.35;99.19; 108.63; 122.21; 122.36; 126.86; 129.13; 130.61; 133.09; 143.53;144.70; 149.76; 155.98; 157.17; 159.27; 172,06.

EXAMPLE 165-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 3-fluoro-4-methoxyaniline according tothe method illustrated in Stages 11i, 11j and 11k of Example 11. Yellowsolid, m.p. >250° C.

NMR-¹H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.08 (d, 1H); 3.49 (d, 1H);4.00 (s, 3H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d,1H); 6.00 (s, 1H);7.32 (s, 1H); 7.72 (d, 1H); 7.91 (d, 1H); 8.58 (s, 1H).

NMR-C¹³ (DMSO): 8.43; 36.48; 42.51; 50.68; 56.60; 61.42; 73.29; 99.25;108.68; 113.52; 122.23; 126.33; 129.99; 130.30; 143.79; 144.70; 148.42;151.18; 153.19; 155.81; 159.20; 172.06.

IR (KBr): 1259; 1503; 1602; 1737.

EXAMPLE 179-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 3-chloro-4-methylaniline according to themethod illustrated in Stages 11i, 11j and 11k of Example 11. Yellowsolid, m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 2.55 (s, 3H); 3.07(d, 1H);3.45 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H);7.39 (s, 1H); 8.10 (s, 1H); 8.20 (s, 1H); 8.60 (s, 1H).

NMR-C¹³ (DMSO): 8.43; 20.20; 36.47; 42.49; 50.67; 61.41; 73.28; 99.87;122.82; 126.98; 127.99; 129.60; 130.53; 131.08; 135.64; 136.56; 144.39;147.11; 153.10; 155.85; 159,18; 172.03.

IR (KBr): 1208; 1479; 1606; 1656; 1724.

EXAMPLE 185-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 3,4-difluoroaniline according to themethod illustrated in Stages 11i, 11j and 11k of Example 11. Yellowsolid; m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d, 1H);5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H);8.15 (q, 1H); 8.25 (q, 1H); 8.68 (s, 1H).

NMR-C¹³ (DMSO): 8.41; 36.45; 42.48; 50.68; 61.40; 73.25; 99.92; 114.44;115.42; 115.58; 122.96; 125.52; 130.56; 131.46; 144.21; 145.25; 142.36;153.41; 155.85; 159.15; 172.00.

IR(KBr): 1266; 1512; 1581; 1618; 1751.

EXAMPLE 197-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione

This compound is obtained from 3,4-methylenedioxyaniline according tothe method illustrated in Stages 11i, 11j and 11k of Example 11. Creamsolid; m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H);5.20 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 6.30 (s, 2H);7.30 (s, 1H); 7.49 (d, 2H); 8.45 (s, 1H).

NMR-C¹³ (DMSO): 8.43; 36.49; 42.56; 50.58; 61.42; 73.31; 98.87; 102.75;103.33; 104.92; 121.76; 125.74; 128.59; 130.33; 145.08; 146.69; 148.78;150.19; 151.49; 155.90; 159.24; 172.08.

IR (KBr): 1248; 1459; 1606; 1731.

EXAMPLE 209-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 3-chloro-4-methoxyaniline according tothe method illustrated in Stages 11i, 11j and 11k of Example 11. Whitesolid; m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H);4.01 (s, 3H); 5.22 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.02 (s, 1H);7.31 (s, 1H); 7.68 (s, 1H); 8.20 (s, 1H); 8.55 (s, 1H).

NMR-C¹³ (DMSO): 8.22; 36.27; 42.30; 50.48; 56.69; 61.23; 73.08; 99.16;107.44; 122.16; 127.12; 128;12; 129.25; 130.02; 130.53; 143.29; 144.37;151.12; 153.29; 155.71; 158.98; 171.84.

IR (KBr): 1056; 1256; 1483; 1592; 1657; 1747.

EXAMPLE 215-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 4-methoxyaniline according to the methodillustrated in Stages 11.i., 11.j. and 11.k. of Example 11. Yellowsolid; m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H);3.95 (s, 3H); 5.28 (s, 2H); 5.40 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H);7.38 (s, 1H); 7.51 (d, 2H); 8.07 (d, 1H); 8.55 (s, 1H).

NMR-C¹³ (DMSO): 8.45; 36.48; 42.51; 50.64; 55.92; 61.42; 73.33; 99.01;106.49; 122.02; 123.19; 129.59; 130.20; 130,43; 144.17; 144.94; 150.40;155.92; 158.31; 159.26; 172.07.

IR((KBr): 1251; 1604; 1655; 1735.

EXAMPLE 229,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 3,5-dichloroaniline according to themethod illustrated in Stages 11.i., 11.j. and 11.k. of Example 11.Yellow solid; m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H);5.30 (s, 2H); 5.41 (d, 1H); 5.55 (d, 1H); 6.08 (s, 1H); 7.41 (s, 1H);8,05 (s, 1H); 8.21 (s, 1H); 8.91 (s, 1H).

NMR-C¹³ (DMSO): 8.39; 36.45; 42.51; 51.03; 61.39; 73.25; 100.62; 123.55;124.63; 127.60; 128.08; 128.56; 132.06; 132.19; 134.53; 143.77; 148.80;154.88; 155.82; 159.13; 171.98.

IR (KBr): 1064; 1275; 1586; 1651; 1743.

EXAMPLE 235-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 3-fluoro-4-methylaniline according to themethod illustrated in Stages 11.i., 11.j. and 11.k. of Example 11.Yellow solid; m.p. >250° C.

NMR-¹H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 2.49 (s, 3H); 3.08 (d, 1H);3.49 (d, 1H); 5.21 (s, 2H); 5.39 (d, 1H); 5.51 (d,1H); 6.05 (s, 1H);7.39 (s, 1H); 7.87 (d, 1H); 8.05 (d, 1H); 8.61 (s, 1H).

NMR-C¹³ (DMSO): 8.40; 15.14; 36.45; 42.52; 50.60; 61.41; 73.28; 99.71;112.00; 122.66; 125.38; 127.66; 129.59; 130.28; 144.49; 147.88; 152.88;155.85; 159.18; 162.25; 172.02.

IR (KBr): 1054; 1580; 1651; 1760.

EXAMPLE 245-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 4-fluoroaniline according to the methodillustrated in Stages 11.i., 11.j. and 11.k. of Example 11. White solid;m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H);5.29 (s, 2H); 5.39 (d, 1H); 5.55 (d, 1H); 6.30 (s, 1H); 7.39 (s, 1H);7.80 (q, 1H); 7.99 (q, 1H); 8.23 (q, 1H);8.68 (s, 1H).

NMR-C¹³ (DMSO): 8.40; 36.46; 42.48; 50.66; 61.41; 73.31; 99.68; 111.83;122.75; 128.93; 130.93; 131.22; 131.93; 144.46; 145.27; 152.60; 155.89;159.21; 172.04.

IR (KBr): 1209; 1589; 1659; 1739.

EXAMPLE 2510-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 4-chloroaniline according to the methodillustrated in Stages 11.i., 11.j. and 11.k. of Example 11. Yellowsolid. m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d, 1H);5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H);7.89 (d, 1H); 8.19 (d, 1H); 8.29 (s, 1H); 8.67 (s, 1H).

NMR-C¹³ (DMSO): 8.40; 36.46; 42.47; 50.70; 61.42; 73.31; 100.00; 122.96;127.31; 127.42; 128.87; 131.11; 132.12; 144.34; 146.53; 153.38; 155.88;159.20; 172.04.

IR (KBr): 1069;1483; 1606; 1741.

EXAMPLE 269-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from 3-chloro-4-fluoroaniline according to themethod illustrated in Stages 11.i., 11.j. and 11.k. of Example 11.Yellow solid. m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H);5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.40 (s, 1H);8.20 (d, 1H); 8.40 (d, 1H); 8.68 (s, 1H).

NMR-C¹³ (DMSO): 8.38; 36.47; 42.58, 50.71; 61.40; 73.26; 99.99; 113.59;123.09; 124.28; 127.74; 130.64; 131.31; 144.13; 145.08; 153.57; 154.13;155.84; 156.61; 159.14; 172.00.

IR (KBr): 1488; 1583; 1655; 1743.

EXAMPLE 275-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

This compound is obtained from morpholine according to the methodillustrated in Example 15.a. White solid, m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.87 (q, 2H); 2.53 (s, 4H); 3.03 (d, 1H);3.45 (d, 1H); 3.57 (s, 4H); 4.02 (s, 2H); 5.01 (s, 2H); 5.38 (d, 1H);5.52 (d, 1H); 6.0 (se, 1H); 7.30 (s, 1H); 7.42 (d, 1H); 7.95 (d, 1H);8.82 (s, 1H).

NMR-C¹³ (DMSO): 8.45; 3.49; 42.58; 53.04; 61.44; 66.33; 73.33; 98.81;113.78; 121.81; 122.74; 126.80; 129.05; 129.91; 143.72; 145.07; 149.24;155.06; 156.92; 159.28; 172.08.

IR(KBr): 1515; 1595; 1654; 1736.

EXAMPLE 285,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

28.a. 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone

This product is obtained according to Sugasawa T; Toyoda T; Adachi M;Sasakura K, J. Am. Chem. Soc., 100 (1978), p.4842-4852). Borontrichloride (1M in heptane, 156 ml, 156 mmol) is added dropwise, underan argon atmosphere at 0° C. to a solution of 3-fluoro-4-methoxy-aniline(20 g, 142 mmol) in anhydrous dichloromethane (200 ml). The pinksuspension thus obtained is maintained under agitation for 5 minutes,then propionitrile (33 ml, 420 mmol) is added dropwise followed byaluminium trichloride (20.8 g, 156 mmol) in small portions. The reactionmedium is heated under reflux for 3 hours, cooled down to 0° C.,hydrolyzed by cautiously adding 2N hydrochloric acid (100 ml), thenheated at reflux for 45 minutes. After cooling down to 0° C. aprecipitate is obtained which is filtered out, washed withdichloromethane, then taken up in water (300 ml). The aqueous phase isbasified to an alkaline pH, extracted with dichloromethane then ethylacetate. The organic phase is dried (MgSO₄) then evaporated to produce acrude product which is purified by column chromatography (SiO₂,AcOEt/Hpt: 1/99 to 20/80). 15.3 g of a yellow solid is obtained.

NMR-¹H (CDCl₃): 1.20 (t, 3H); 2.92 (q, 2H); 3.83 (s, 3H); 6.2 (s, 2H);6.40 (d, 2H); 7.32 (d, 2H).

IR (KBr): 857; 1148; 1240; 1561; 1583; 1662.

28.b. ethyl4-ethyl-7-fluoro-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate

A solution of ethylmalonyl chloride (12.9 ml, 100 mmol) in anhydrousacetonitrile (30 ml) is added dropwise, under argon and at 0° C. to asolution of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone (15.3 g,77.5 mmol) and triethylamine (13.9 ml, 100 mmol) in anhydrousacetonitrile (110 ml). The reaction medium is left to return to ambienttemperature, a solution of sodium ethylate (obtained by 1.8 g, 78 mmolof sodium in 80 ml of ethanol) is cannulated dropwise and under argon,then the reaction medium is left under agitation for 12 hours at ambienttemperature. The reaction mixture is poured into ice-cooled water (100ml) and agitation is carried out for two hours, then the precipitate isfiltered out and washed with water, with ethanol and with ether. 19.4 gof a white solid is obtained.

NMR-¹H (DMSO): 1.25 (m, 6H); 2.78 (q, 2H); 3.92 (s, 3H); 4.30 (q, 2H);7.15 (d, 2H); 7.40 (d, 2H); 11.93 (s, 1H).

IR (KBr): 786; 1083; 1410; 1521; 1644; 1725.

28.c. ethyl 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate

A suspension of ethyl4-ethyl-7-fluoro-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate(19.4 g, 0.066 mol) in phosphoryl chloride (243 ml) is heated at refluxfor 6 hours. The phosphoryl chloride is distilled off. The reactionmixture is decanted into ice-cooled water, then taken up indichloromethane to solubilize. The organic phase is washed with water,then with a saturated solution of sodium chloride. The organic phase isdried over magnesium sulphate and the solvent is evaporated off. Theresidue is suspended in ether and the non-converted starting product (4g) is filtered out. The filtrate is evaporated and the residue ispurified by column chromatography (SiO₂, AcOEt/Hpt: 5/95 to 20/80). 10.9g of a white solid is obtained.

NMR-¹H (DMSO): 1.30 (t, 3H); 1.39 (t, 3H); 3.08 (q, 2H); 4.09 (s, 3H);4.49 (q, 2H); 7.64 (d, 2H); 7.86 (d, 2H).

IR (KBr): 865; 1016; 1082; 1190; 1224; 1253; 1272; 1508; 1571; 1732.

28.d. (2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinyl)methanol

A solution of ethyl2-chloro-4-ethyl-7-fluoro-6-methoxy-3quinolinecarboxylate (10.8 g, 35mmol) in anhydrous dichloromethane (200 ml) is treated dropwise atambient temperature under an inert atmosphere with diisobutylaluminiumhydride (1M in dichloromethane, 65 ml, 65 mmol), then heated at 40° C.for 4 hours. After cooling down to 0° C., a 20% aqueous solution ofRochelle salt (105 ml) and dichloromethane (200 ml) are added cautiouslyand the reaction mixture is maintained under agitation for 1 hour,followed by decanting and washing three times with water. The organicphase is dried over magnesium sulphate and the solvent is evaporatedoff. The residue is purified by column chromatography (SiO₂, AcOEt/Hpt:5/95 to 50/50). 6 g of a white solid is obtained.

NMR-¹H (DMSO): 1.28 (t, 3H); 3.25 (q, 2H); 4.04 (s, 3H); 4.77 (d, 2H);5.27 (t, 1H); 7.55 (d, 2H); 7.73 (d, 2H).

IR (KBr): 840; 864; 1023; 1232; 1267; 1317; 1444; 1511; 1569.

28.e.5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

(2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinyl)methanol is coupledwith compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the proceduredescribed in Stage 11.k. A yellow solid is obtained, m.p. >275° C.

NMR-¹H (CF3COOD): 1.07 (m, 3H); 1.62 (m, 3H); 2.27 (m,2H); 3.44 (d, 1H);3.54 (m, 2H); 3.91 (d, 1H); 4.25 (s, 3H); 5.60 (d, 1H); 5.74 (s, 2H);5.98 (d, 1H); 7.85 (m, 1H); 8.16 (m, 1H); 8.31 (s, 1H).

NMR-C¹³ (CF3COOD): 9.03; 14.20; 26.68; 38.77; 43.98; 53.79; 58.27;64.73; 77.93; 106.85; 109.24; 110.15; 128.99; 129.20; 131.61; 137.32;141.23; 144.13; 154.79; 158.32; 160.25; 160.81; 179.30.

IR (KBr): 1013; 1068; 1265; 1466; 1514; 1601; 1655; 1748.

EXAMPLE 295-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 28.b., 28.c. and 28.d. is applied to2-acetylaniline in order to produce(2-chloro-4-methyl-3-quinolinyl)methanol. The latter coupled to compound(M) as described in Stage 11.j. of Example 11. The resultant coupledproduct is cyclized according to the procedure of Stage 11.k. A yellowsolid is obtained, m.p. >260° C.

NMR ¹H (DMSO): 0.87 (t, 3H); 1.87 (q, 2H); 2.78 (s, 3H); 2.80 (d, 1H);3.55 (d, 1H); 5.27 (s, 2H); 5.42 (d, 1H); 5.52 (d, 1H); 6.04 (s, 1H);7.39 (s, 1H); 7.75 (t, 1H); 7.88 (t, 1H); 8.13 (d, 1H); 8.25 (d, 1H).

NMR-C¹³ (DMSO): 8.23; 36.26; 42.36; 62.00; 73.11; 78.65; 79.13; 79.25;99.52; 122.36; 124.30; 127.67; 129.54; 129.55; 129.56; 140.11; 145.06;148.07; 152.00; 155.79; 159.09; 171.89.

IR (KBr): 1649; 1751; 3404.

EXAMPLE 309-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

30.a. 5-chloro-2-chloroacetyl-4-methoxyaniline

This product is obtained according to Sugasawa T; Toyoda T; Adachi M;Sasakura K, J. Am. Chem. Soc., 100 (1978), p.4842-4852. A molar solutionof boron trichloride in hexane (164 ml, 164 mmol), chloroacetonitrile(11,4 ml, 180 mmol), and a molar solution of diethylaluminium chloridein hexane (164 ml, 164 mmol), are added dropwise and successively underan inert atmosphere at 0° C. to a solution of 3-chloro-4-methoxyaniline(23.6 g, 150 mmol). The reaction medium is heated under reflux for 1hour, cooled down to 0° C., hydrolyzed by cautiously adding 2Nhydrochloric acid (90 ml), then heating to reflux for 1 hour. Thereaction medium is cooled down and a concentrated soda solution is addeduntil pH 14. Extraction is carried out with ethyl acetate, the organicphase is washed with water, then with salt water. Followed by dryingover magnesium sulphate, filtering and evaporating under reducedpressure. The residue is taken up in isopentane, followed by decanting,then the insoluble part is taken up in the minimum amount of isopropylether, isopentane is added in order to precipitate the product, followedby filtering and drying under vacuum. 17.26 g of a brown solid isobtained.

NMR-¹H (CDCl₃): 3.82 (s, 3H); 4.60 (s, 2H); 6.11 (s, 2H); 6.78 (s, 1H));7.11 (s, 1H),

30.b. ethyl7-chloro-4-(chloromethyl)-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate

A solution of ethylmalonyl chloride (17 ml, 131 mmol) is added dropwiseunder argon and at 0° C. to a solution of5-chloro-2-chloroacetyl-4-methoxyaniline (17 g, 73 mmol) andtriethylamine (18.5 ml, 131 mmol) in anhydrous acetonitrile (310 ml).Agitation is carried out for 2 hours at ambient temperature, then asolution of sodium ethanolate in ethanol (obtained by 1.88 g, 80 mmol,of sodium in 90 ml of ethanol) is added dropwise at 0° C. Agitation iscarried out for 12 hours at ambient temperature 300 ml of water isadded, and agitation is again carried out for 20 minutes. Theprecipitate is filtered out; washed with water, with ethanol, and withethyl ether. After drying under vacuum 16.7 g of a yellowish solid isobtained.

NMR-¹H (DMSO): 1.31 (t, 3H); 3.95 (s, 3H); 4.36 (q, 2H); 4.95 (s, 2H);7.46 (s, 1H); 7.49 (s,1H).

30.c. ethyl2,7-dichloro-4-(chloromethyl)-6-methoxy-3-quinolinecarboxylate

A suspension of ethyl7-chloro-4-(chloromethyl)-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate(116.7 g, 50 mmol) in phosphoryl chloride (100 ml) is heated to refluxfor 6 hours. The phosphoryl chloride is distilled off. The residue istaken up in water and agitation is carried out for 30 min. Theprecipitate is filtered out and washed with water until neutrality. Theprecipitate is taken up in dichloromethane and with a saturated solutionof sodium chloride. After filtering through a bed of celite the filtrateis decanted. The organic phase is washed again with a saturated solutionof sodium chloride, followed by drying over magnesium sulphate,filtering and evaporating under reduced pressure. 15.88 g of a brown oilis obtained.

NMR-¹H (CDCl₃): 1.47 (t, 3H); 4.08 (t, 3H); 4.55 (q, 2H); 4.87 (s, 2H);7.35 (s 1H); 8.09 (s, 1H).

30.d. ethyl2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinecarboxylate

A mixture of ethyl2,7-dichloro-4-(chloromethyl)-6-methoxy-3-quinolinecarboxylate (6.9 g,20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated to 60° C. for30 min. The reaction mass is diluted with water and extraction iscarried out with ethyl acetate. After decanting, the organic phase iswashed with water, followed by drying over magnesium sulphate, filteringand evaporating under reduced pressure. The residue is taken up inwater, agitated for 15 minutes, filtered, washed with water and driedunder vacuum. The residue is purified by column chromatography (SiO₂,MeOH/CH₂Cl₂: 5/95 to 8/92). 6.7 g of product, a beige solid, isobtained.

NMR-¹H (CDCl₃): 1.45 (t, 3H); 2.28 (s, 3H); 2.35-2.70 (m, 8H); 3.86 (s,2H); 4.04 (s, 3H); 4.48 (q, 2H); 7.77 (s, 1H); 8.05 (s, 1H).

30.e.{2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinyl}methanol

ethyl2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinecarboxylate(6 g, 14.5 mmol) is dissolved in methylene chloride (120 ml). A molarsolution of diisobutylaluminium hydride in methylene chloride (60 ml, 60mmol) is added slowly. Agitation is carried out for one hour at ambienttemperature. The reaction mass is slowly poured into 300 ml of a 20%solution of Rochelle salt. Agitation is carried out for one hour,followed by filtering on celite and decanting; the organic phase iswashed with a saturated solution of sodium chloride, dried overmagnesium sulphate, filtered and evaporated under reduced pressure. Thesolid is taken up in isopropyl ether, filtered and dried under vacuum.4.3 g of sought product (80%) is obtained, in the form of a yellowsolid.

NMR-¹H (CDCl₃): 2.27 (s, 3H); 2.30-2.80 (m, 8H); 4.03 (s, 3H); 4.08 (s,2H); 4.96 (s, 2H); 5.95 (s, 1H); 7.37 (s, 1H); 8.05 (s, 1H).

30.f.9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

{2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinyl}-methanolis coupled to compound (M) as described in Stage 11.j. of Example 11.The resultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p. >250° C.

NMR-¹H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.53 (s, 4H); 3.08 (d, 1H);3.47 (d, 1H); 3.58 (s, 4H); 4.06 (s, 5H); 5.30 (s, 2H); 5.42 (q, 2H);6.03 (s, 1H); 7.31 (s, 1H); 7.91 (s, 1H); 8.16 (s, 1H).

NMR-C¹³ (DMSO): 8.42; 36.53; 50.65; 53.30; 56.67; 62.00; 66.50; 73.32;99.31; 104.86; 122.32; 126.94; 127.70; 129.83; 130.44; 138.89; 144.22;144.85; 151.05; 153.17; 155.92; 159.19; 172.06.

IR (KBr): 862; 1063; 1116; 1248; 1595; 1655; 1744; 3449.

EXAMPLE 319-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methoxyaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6methoxy-3-quinoline-carboxylate which istreated according to the procedure of Example 30.d., by using morpholineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled to compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11k. A beige solid is obtained, m.p. >250° C.

NMR-¹H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.15 (s, 3H); 2.32 (s, 4H);2.50 (s, 4H); 3.08 (d, 1H); 3.47 (d, 1H); 4.06 (s, 5H); 5.29 (s, 2H);5.46 (q, 2H); 6.06 (s, 1H); 7.31 (s, 1H); 7.92 (s, 1H); 8.17 (s, 1H).

NMR-C¹³ (DMSO): 8.42; 36.51; 42.57; 45.93; 50.66; 52.83; 55.05; 56.09;56.72; 61.44; 73.29; 99.30; 104.89; 122.32; 126.89; 127.63; 129.85,130.16; 138.78; 144.18; 144.81; 151.03; 153.10; 155.10; 159.17; 172.07.

IR (KBr): 1055; 1252; 1596; 1655; 1747; 3449.

EXAMPLE 325-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied toaniline in order to produce ethyl2-chloro-4-chloromethyl-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., with N-methylpiperazine,then reduced according to the method of Example 30.e. into thecorresponding quinolinemethanol. The latter is coupled to compound (M)as described in Stage 11.j. of Example 11. The resultant coupled productis cyclized according to the procedure of Stage 11.k. A yellow solid isobtained, m.p. >260° C.

NMR-¹H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 2.14 (s, 3H); 2.32-2.60 (m,8H); 3.05 (d, 1H); 3.48 (d, 1H); 4.09 (q, 2H); 5.42 (d, 1H); 5.52 (d,1H); 6.03 (se, 1H); 7.40 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H); 8.16 (d,1H); 8.45 (d, 1H).

IR (KBr): 1652; 1735; 3424.

EXAMPLE 335-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied toaniline in order to produce ethyl 2-chloro-4-chloromethyl-3-quinolinecarboxylate which is treated according to the procedure of Example30.d., by using piperidine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled to compound (M) as described inStage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. >260° C.

NMR-¹H (DMSO): 0.86 (t, 3H); 1.40 (se, 2H); 1,48 (se, 4H); 1.87 (q, 2H);2.50 (s, 4H); 3.05 (d, 1H); 3.48 (d, 1H); 4.04 (q, 2H); 5.33 (s, 2H);5.42 (d, 1H); 5.51 (d, 1H); 6.07 (se, 1H); 7.75 (t, 1H); 7.85 (t, 1H);8.15 (d, 1H); 8.45 (d, 1H).

NMR-C¹³ (DMSO): 8.47; 23.50; 25.82; 36.50; 42.50; 50.68; 54.47; 58.00;61.42; 73.35; 99.55; 122.61; 125.31; 127.58; 129.54; 129.55; 129.56;129.57; 140.49; 144.95; 148.63; 152.41; 155.90; 159.23: 172.07.

IR (KBr): 1659; 1727; 3408.

EXAMPLE 345-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied toaniline in order to produce ethyl2-chloro-4-chloromethyl-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., by using morpholine insteadof N-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Ayellow solid is obtained, m.p. >260° C.

NMR-¹H (DMSO): 0.86 (t, 3H); 1.87 (q, 2M); 3.05 (d, 1H); 3.30 (s, 4H);3.49 (d, 1H); 3.55 (se, 4H); 4.10 (q, 2H); 5.35 (s, 2H); 5.40 (d, 1H);5.54 (d, 1H); 6.04 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H); 8.16 (d, 1H);8.47 (d, 1H).

NMR-C¹³ (DMSO): 8.42; 36.51; 42.57; 50.68; 53.51; 56.06; 61.42; 66.41;73.34; 99.56; 122.64; 125.25; 127.56; 129.81; 139.55; 144.92; 148.62;152.39; 155.89; 159.21; 172.05.

IR (KBr): 1657; 1729; 3347.

EXAMPLE 355-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-fluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d. with N-methylpiperazine,then reduced according to the method of Example 30.e. into thecorresponding quinolinemethanol. The latter is coupled to compound (M)as described in Stage 11.j. of Example 11. The resultant coupled productis cyclized according to the procedure of Stage 11.k. A yellow solid isobtained, m.p. >275° C.

NMR-¹H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.15 (s, 3H); 2.31 (m, 4H);2.50 (m, 4H); 3.07 (d, 1H); 3.48 (d, 1H); 4.04 (m, 2H); 5.31 (s, 2H);5.40 (d, 1H); 5.53 (d, 1H); 6.05 (s, 1H); 7.38 (s, 1H); 7.77 (m, 1H);8.19 (m, 2H).

NMR-C¹³ (DMSO): 8.43; 36.51; 42.54; 45.89; 50.67; 52.92; 54.93; 55.92;73.32; 99.56; 122.69; 130.43; 132.40; 139.69; 144.70; 145.84; 152.19;155.90; 159.17; 172.05.

IR (KBr): 836; 1051; 1217; 1291; 1612; 1662; 1726.

EXAMPLE 365-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-fluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., by using morpholine insteadof N-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Abeige solid is obtained, m.p. >250° C.

NMR-¹H (DMSO): 0.87 (m, 3H); 1.85 (m, 2H); 2.51 (m,4H); 3.06 (d, 1H);3.48 (d, 1H); 3.56 (m, 4H); 4.05 (m, 2H); 5.34 (s, 2H); 5.40 (d, 1H);5.53 (d, 1H); 6.04 (s, 1H); 7.38 (s, 1H); 7.77 (m, 1H); 8.21 (m, 2H).

NMR¹³ (DMSO): 8.40; 36.47; 42.52; 50.59; 53.40; 56.14; 61.44; 66.41;73.29; 99.58; 109.05; 109.28; 120.11; 120.37; 122.68; 128.53; 130.53;132.43; 139.13; 144.62; 145.79; 152.07; 155.94; 159.14; 161.59; 172.04.

IR (KBr): 834; 860; 1061; 1118; 1215; 1286; 1516; 1609; 1658; 1734.

EXAMPLE 375-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d. withN-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Ayellow solid is obtained, m.p. >260° C.

NMR-¹H (CDCl₃): 1.00 (t, 3H); 2.00 (q, 2H); 2.35 (s, 3H); 2.50 (s, 3H);2.61 (m, 8H); 3.33 (d, 1H); 3.39 (d, 1H); 3.97 (d, 1H); 4.07 (d, 1H);5.17 (d, 1H); 5.38 (d, 1H); 5.52 (d, 1H); 5.63 (d, 1H); 7.13 (d, 1H);7.28 (s, 1H); 7.99 (d, 1H).

IR (KBr): 1652; 1747; 3430.

EXAMPLE 385-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxe;pino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a, 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., by usingmorpholine instead of N-methylpiperazine, then reduced according to themethod of Example 30.e. into the corresponding quinolinemethanol. Thelatter is coupled to compound (M) as described in Stage 11.j. of Example11. The resultant coupled product is cyclized according to the procedureof Stage 11.k. A yellow solid is obtained, m.p. >260° C.

NMR-¹H (DMSO+CDCl₃): 1.00 (t, 3H); 2.02 (q, 2H); 2.57 (s, 3H); 2.60 (s,4H); 3.23 (d, 1H); 3.45 (d, 1H); 3.75 (s, 4H); 4.11 (s, 2H); 5.44 (s,2H); 5.47 (d, 5.65 (d, 1H); 7.62 (s, 1H); 7.73 (d, 1H); 8.24 (d, 1H).

NMR-C¹³ (CF₃CO₂D): 8.35; 13.93; 16.01; 22.24; 25.29; 38.18; 43.42;54.19; 56.04; 56.74; 64.16; 65.09; 77.48; 108.29; 108.57; 128.07;128.70; 129.90; 135.64; 138.03; 139.86; 141.10; 141.56; 147.78; 158.30;161.87; 178.72.

IR (KBr): 117; 1609; 1654; 1750; 3437.

EXAMPLE 395-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., by usingpiperidine instead of N-methylpiperazine, then reduced according to themethod of Example 30.e. into the corresponding quinolinemethanol. Thelatter is coupled to compound (M) as described in Stage 11.j. of Example11. The resultant coupled product is cyclized according to the procedureof Stage 11.k. A yellow solid is obtained, m.p. >260° C.

NMR-¹H (CF₃CO₂D): 1.09 (s, 3H); 1.70 (t, 1H); 2.03 (m, 5H); 2.25 (s,2H); 2.70 (s, 3H); 3.54 (d, 3H); 3.88 (d, 1H); 4.01 (se, 2H); 5.30 (q,2H); 5.65 (d, 1H); 5.96 (d, 1H); 6.10 (s, 2H); 8.16 (d, 1H); 8.35 (s,1H); 8.61 (s, 1H).

NMR-C¹³ (CF₃CO₂D): 8.47; 16.07; 20.93; 22.18; 24.76; 38.28; 43.53;54.30; 56.12; 58.33; 64.24; 77.56; 108.37; 111.30; 128.20; 129.02;129.98; 135.60; 138.29; 139.90; 141.60; 142.26; 147.57; 158.28; 161.90;167.63; 170.31; 178.82.

IR (KBr): 1605; 1657; 1728; 3399.

EXAMPLE 408-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3,4-ethylenedioxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-ethylenedioxy-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d. withN-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Ayellow solid is obtained, m.p. >260° C.

NMR-¹H (DMSO): 0.92 (t, 3H); 1.89 (q, 2H); 2.16 (s, 3H); 2.50 (m, 8H);3.12 (d, 1H); 3.50 (d, 1H); 3.95 (s, 2H); 4.47 (s, 4H); 5.19 (q, 2H);5.43 (d, 1H); 5.56 (d, 1H); 7.35 (s, 1H); 7.54 (s, 1H); 7.76 (s, 1H).

NMR-C¹³ (DMSO): 8.45; 24.80; 36.51; 42.48; 45.90; 50.45; 52.98; 54.91;56.10; 61.44; 64.43; 73.30; 99.03; 109.46; 113.51; 121.95; 123.51;127.76; 137.99; 145.00; 145.14; 145.27; 147.24; 150.53; 155.99; 159.18;172.27; 177.00.

IR (KBr): 1656; 1743; 3422.

EXAMPLE 419-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-fluoroaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., by using morpholineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled to compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A beige solid is obtained, m.p. >250° C.

NMR-¹H (CF₃COOD): 1.09 (t, 3H); 2.30 (m, 2H); 3.50 (d, 1H); 3.90 (d,1H); 3.98 (d, 4H); 4.36 (s, 4H); 5.38 (q, 2H); 5.64 (d, 1H); 5.96 (d,1H); 6.23 (q, 2H); 8.57 (d, 1H); 8.60 (s, 1H); 8.85 (d, 1H).

NMR-C¹³ (CF₃COOD): 8.10; 37.80; 43.11; 54.31; 55.78; 63.75; 65.11;77.06; 128.28; 129.55; 130.33; 136.26; 137.11; 138.40; 139.67; 139.85;148.58; 157.54; 159.74; 161.31; 178.00.

IR (KBr): 848; 1042; 1230; 1609; 1658; 1750; 3310; 3387.

EXAMPLE 42 Resolution of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

A mixture of 3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoic acid (19.5 g, 51 mmol) andL-(−)-α-methylbenzylamine (12.12 g, 100 mmol) in absolute ethanol (1 l)is heated to boiling, followed by filtering while warm and leaving atrest for 68 hours. The precipitate is filtered and washed with ethanoland with ether to produce 9.8 g of a white solid. Analysis by highpressure liquid chromatography on the chiral stationary phase (“ChiralHPLC” on Chiral-AGP column (Chromtech, Stockholm, Sweden) 100×4 mm,eluant 2% acetonitrile in 10 mM phosphate buffer at pH 6.9, peakseluting at 4.5 and 7.5 min) reveals two peaks integrating respectively24% and 76% of the total area of the two peaks. The solid is taken up in93% ethanol (350 ml) under reflux, then left at rest for 48 hours. Theprecipitate is filtered out then washed with ethanol and with ether inorder to obtain 4.8 g of a white solid which produces two peaksintegrating respectively 9% and 91% of the total area of the two peaksusing chiral HPLC. The solid is taken up in 50% ethanol (48 ml) underreflux then left at rest for 48 hours. The precipitate is filtered outthen washed with ethanol and with ether in order to produce 2.7 g of awhite solid which produces two peaks integrating respectively 3% and 97%of the total area of the two peaks using chiral HPLC. The solid is takenup in 50% ethanol (22 ml) under reflux then left at rest for 48 hours.The precipitate is filtered out then washed with ethanol and with etherin order to produce 1.6 g of a white solid which produces two peaksintegrating respectively 1% and 99% of the total area of the two peaksusing chiral HPLC. The resultant salt, diastereoisomerically enriched,taken up in distilled water (20 ml), is treated with acetic acid (0.35ml, 6.4 mmol) for 15 minutes. The precipitate obtained is filtered out,washed with water, with acetone and with ether, then dried under vacuumat 80° C. in order to obtain 1.1 g of a white solid. The latter is takenup in absolute ethanol (55 ml) with concentrated hydrochloric acid (11.5N, 11 ml) added to it in order to obtain a yellow solution which ismaintained under agitation at ambient temperature for 68 hours. Theprecipitate thus obtained is filtered out and washed with water, withethanol and with ether, then dried under vacuum at 80° C. in order toobtain 770 mg of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionewhich is enantiomerically enriched. Analysis by chiral HPLC (Chiral-AGPcolumn, eluted with a 2 to 5% gradient of acetonitrile in 10 mMphosphate buffer at pH 6.9, peaks eluting at 15 and 20 minutes) revealsan enantiomeric excess of 98%. The procedure described above is carriedout again replacing the L-(−)-α-methylbenzylamine withD-(+)-α-methylbenzylamine. In this way the other enantiomer of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneis obtained.

EXAMPLE 4312-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinoline carboxylate, which istreated according to the procedure of Example 30.d., using1,2,3,6-tetrahydropyridine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11 .j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. The free base thus obtained issuspended in absolute ethanol (50 ml/mmol) then treated with ethanolichydrogen chloride (2.5N, 5 equ.). Initially a yellow solution forms,then a precipitate which is collected by filtering after concentrationto 40% of initial volume, and washed with ether. A light orange solid isobtained, m.p. 264° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.26-2.30 (m, 1H); 2.50 (m,1H); 3.09 (d, 1H); 3.40 (m, 2H); 3.48 (d, 1H); 3.87 (m, 2H); 5.05 (m,2H); 5.48 (q, 2H); 5.65 (m, 2H); 5.89 (m, 1H); 7.42 (s, 1H); 8 24-8.30(m, 1H); 8.76-8.82 (m, 1H); 10.86 (s, 1H).

NMR-C13 (DMSO): 8.44; 22.36; 36.5; 42.7; 48.71; 50.30; 51.49; 61.42;73.23; 100.16; 112.64; 112.83; 116.05; 120.26; 123.31; 125.29; 125.40;131.17; 133.97; 144.15; 146.26; 146.37; 148.74, 150.52; 151.23; 153.20;153.53; 155.99; 159.04; 172.02.

IR (KBr): 662; 1064; 1268; 1452; 1523; 1598; 1652; 1743; 2936; 3027;3418.

EXAMPLE 445-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A beige solid is obtained, m.p. >250° C.

NMR-1H (DMSO): 0.9 (m, 6H); 1.1 (m, 2H); 1.4 (m, 1H); 1.55 (d, 2H). 1.85(q, 2H); 2.1 (t, 2H); 2.85 (m, 2H); 3.25 (dd, 2H); 4 (s, 2H); 5.3 (s,2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 8.15 (dd, 1H); 8.45 (dd,1H).

IR (KBr): 1454; 1518; 1608; 1658; 1733; 2804; 2926; 3311.

Suspension of the above free base in absolute ethanol (50 ml/mmol)followed by treatment with ethanolic hydrogen chloride (2.5 N, 5 equ.)allows the corresponding hydrochloride to be obtained. Initially, ayellow solution forms, then a precipitate which is collected byfiltering after concentration to 40% of the initial volume, then washedwith ether. A vivid orange solid is obtained, m.p. >250° C.

NMR-1H (DMSO): 0.85 (m, 6H); 1.7 (m, 5H); 1.85 (q, 2H); 3.15 (s, 1H);3.25 (dd, 2H); 3,3 (m, 2H); 4.9 (s, 2H); 5.45 (dd, 2H); 5.6 (s, 2H); 6.1(s, 1H); 7.4 (s, 1H); 8.25 (dd, 1H); 8.75 (dd, 1H); 10.35 (s, 1H).

IR (KBr): 1270; 1455; 1523; 1606; 1653; 1742; 2943; 3419.

EXAMPLE 455-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using pyrrolidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A beige solid is obtained, m.p. >250° C.

NMR-1H (DMSO): 0.85 (t, 3H); 1.7 (s, 4H); 1,85 (q, 2H); 2,55 (s, 4H);3.25 (dd, 2H); 4.15 (d, 2H); 5.35 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H);7.35 (s, 1H); 8.15 (dd, 1H); 8.45 (dd, 1H).

IR (KBr): 1455; 1518; 1605; 1657; 1731; 2801; 2970; 3422.

Suspension of the above free base in absolute ethanol (50 ml/mmol)followed by treatment with ethanolic hydrogen chloride (2.5 N, 5 equ.)allows the corresponding hydrochloride to be obtained. Initially, ayellow solution forms, then a precipitate which is collected byfiltering after concentration to 40% of the initial volume, then washedwith ether. A light orange solid is obtained, m.p. >250° C.

NMR-¹H (DMSO): 0.85 (t, 3H); 1.9 (m, 4H); 2.1 (s, 2H); 3.25 (dd, 2H);3.3 (m, 2H); 3.55 (m, 2H); 5.05 (s, 2H); 5.45 (dd, 2H); 5.6 (s, 2H); 6.1(s, 1H); 7.4 (s, 1H); 8.3 (dd, 1H); 8.75 (dd, 1H); 10.75 (s, 1H).

IR (KBr): 1454; 1522; 1603; 1653; 1743; 2970; 3394.

EXAMPLE 465-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline3,15dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. >250° C.

NMR-1H (CDCl₃+CD₃OD): 0.99 (t, 3H); 2.00 (q, 2H); 2.32 (s, 3H); 3.24 (d,1H); 3.37 (s, 1H); 3.42 (d, 1H); 4.04 (s, 2H); 5.37 (s, 2H); 5.43 (d,1H); 5.64 (d, 1H); 7.56 (s, 1H); 7.84 (dd, 1H); 8.22 (dd, 1H).

NMR-C13 (CDCl₃+CD₃OD): 7.87; 36.11; 42.16; 45.33; 52.67; 54.52; 56.47;61.97; 73.26; 101.17; 110.81; 115.49; 122.93; 128.63; 139.83; 144.28;146.40; 149.27; 151.27; 151.64; 152.31; 153.82; 156.50; 159.71; 172.56.

IR (KBr): 1607; 1656; 1732; 2795; 3411.

EXAMPLE 475-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A light green solid is obtained, m.p. 266-268° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.42-1.49 (m, 6H); 1.85 (q, 2H); 2.47 (m,4H); 3.06 (d, 1H); 3.48 (d, 1H); 4.00 (q, 2H); 5.31 (s, 2H); 5.46 (dd,2H); 6.04 (s, 1H); 7.37 (s, 1H); 8.14 (m, 1H); 8.46 (m, 1H).

NMR-C13 (DMSO): 8.43; 24.01; 25.8; 36.52; 42.56; 50.60; 54.29; 56.91;61.41; 73.30; 99.81; 111.86; 115.67; 122.94; 130.10; 140.66; 144.49;146.12; 153.18; 155.86;. 159.14; 172.03.

IR (KBr): 1258; 1452; 1517; 1607; 1661; 1731; 2950; 3480.

EXAMPLE 4812-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using dimethylamineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A light beige solid is obtained, m.p. >270° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.25 (s, 6H); 3.08 (d, 1H);3.47 (d, 1H); 3.95 (q, 2H); 5.28 (s, 2H); 5.46 (dd, 2H); 6.06 (s, 1H);7.37 (s, 1H); 8.14 (s, 1H); 8.42 (s, 1H).

NMR-C13 (DMSO): 8.42; 14.06; 33.36; 45.44; 50.57; 61.40; 65.14; 72.05;72.93; 73.30; 99.82; 99.95; 115.78; 115.85; 122.96; 125.01; 130.08;140.56; 144.54; 146.16; 155.86; 159.19; 172.03.

IR (KBr): 1516; 1613; 1654; 1731; 3450.

EXAMPLE 499-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using morpholineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>300° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.50 (s, 4H); 2.58 (s, 3H);3.07 (d, 1H); 3.46 (d, 1H); 3.57 (s, 4H); 4.08 (dd, 2H); 5.30 (s, 2H);5.51 (dd, 2H); 6.06 (s, 1H); 7.35 (s, 1H); 8.15 (s, 1H): 8.41 (s, 1H).

NMR-C13 (DMSO): 8.42; 20.57; 36.51; 42.55; 50.76; 53.46; 55.86; 61.42;66.42; 73.29; 99.73; 122.78; 128.40; 130.10; 135.31; 136.26; 139.36144.61; 147.79; 152.81; 155.86; 159.16; 172.04.

IR (KBr): 1613; 1657; 1736; 3432.

EXAMPLE 509-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. 262-268° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.86 (q, 2H); 2.15 (s, 3H); 2.20-260 (m,8H); 2.60 (s, 3H); 3.05 (d, 1H); 3.49 (d, 1H); 4.09 (dd, 2H); 5.32 (s,2H); 5.50 (dd, 2H); 6.05 (s, 1H); 7.37 (s, 1H); 8.21 (s, 1H); 8.43 (s,1H).

NMR-C13 (DMSO): 8.42; 20.56; 36.50; 42.55; 45.91; 50.81; 53.00; 54.94;55.65; 61.43; 73.29; 79.36; 99.69; 122.75; 126.32; 128.37; 129.84;135.25; 136.23; 139.87; 144.57; 147.75; 152.76; 155.87; 159.15; 172.04.

IR (KBr): 1607; 1658; 1733; 3424.

EXAMPLE 5112-{[benzyl(methyl)amino]methyl}-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., usingN-methylbenzylamine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. 275-278° C.

NMR-1H (DMSO): 0.88 (t, 3H); 1.85 (m, 2H); 2.13 (s, 3H); 2.55 (s, 3H);3.10 (d, 1H); 3.50 (d, 1H); 3.67 (s, 2H); 4.05 (dd, 2H); 5.30 (s, 2H);5.39-5.57 (dd, 2H); 6.05 (s, 1H); 7.36 (m, 6H); 8.15 (s, 1H); 8.31 (s,1H).

NMR-C13 (DMSO): 9.10; 21.15; 37.20; 42.86; 43.23; 51.32; 55.78; 62.10;62.88; 73.99; 80.05; 100.44; 123.47; 126.99; 127.32; 128.09; 129.17;129.96; 130.86; 135.75; 136.84; 139.51; 140.67; 145.38; 148.54; 153.50;156.54; 159.85: 172.73.

IR(KBr): 1609; 1655; 1729; 3395.

EXAMPLE 5212-[(4-benzyl-1-piperazinyl)methyl]-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methylaniline; in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., usingN-benzylpiperazine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A beige solid is obtained, m.p. 244-249° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.83 (m, 2H); 2.38-2.60 (m, 8H); 2.57 (s,3H); 3.08 (d, 1H); 3.46 (s, 2H); 4.08 (m, 2H); 5.30 (s, 2H); 5.51 (dd,2H); 6.05 (s, 1H); 7.30 (m, 6H); 8.16 (s. 1H); 8.40 (s, 1H).

NMR-C13 (DMSO): 9.10; 21.23; 37.19; 43.21; 51.48; 53.54; 53.80; 56.35;62.09; 62.84; 73.97; 97.67; 100.39; 123.45; 127.05; 127.75; 129.02129.63; 130.61; 135.95; 136.93; 139.14; 140.52; 145.27; 148.45; 153.47;156.52; 159.83; 172.72.

IR (KBr): 1567; 1587; 1652; 1748; 3422.

EXAMPLE 539-chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p. 255° C. (dec).

NMR-1H (DMSO): 0.86 (t, 3H); 1.50 (m, 6H); 1.84 (m, 2H); 2.50 (m, 4H);2.58 (s, 3H); 3.05 (d, 1H); 3.45 (d, 1H); 4.04 (m, 2H); 5.32 (s, 2H);5.51 (dd, 2H); 6.10 (s, 1H); 7.37 (s, 1H); 8.20 (s, 1H); 8.42 (s, 1H).

NMR-C13 (DMSO): 9.11; 21.24; 24.70; 26.50; 37.20; 43.23; 51.43; 55.10;57.21; 62.09; 73.99; 98.05; 100.38; 123.44; 127.10; 129.12; 130.59;135.89; 136.91; 140.99; 145.31; 148.50; 153.52; 156.51; 159.85; 172.73.

IR (KBr): 1601; 1654; 1728; 3436.

EXAMPLE 5412-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-fluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., using N-benzylpiperazineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A white solid is obtained, m.p. 262° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.37 (s, 4H); 2.37 (s, 4H);3.07 (d, 1H); 3.45 (s, 2H); 3.47 (d, 1H); 4.08 (q, 2H); 5.32 (s, 2H);5.46 (dd, 2H), 6.03 (s, 1H); 7.35 (m, 5H); 7.38 (s, 1H); 7.77 (m, 1H);8.20 (m, 2H).

NMR-C13 (DMSO): 8.41; 36.49; 42.53; 50.65; 52.82; 53.03; 55.95; 61.41;62.14; 72.3; 99.55; 109.31; 120.14; 120.40; 122.70; 127.05; 128.32128.55; 128.96; 130.40; 138.42; 139.65; 144.66; 145.83; 152.15; 155.89;159.15; 161.57; 172.02.

IR (KBr): 740; 834; 1071; 1193; 1220; 1288; 1360; 1451: 1516; 1592;1655; 1749; 2813; 2950; 3434.

EXAMPLE 5512-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., usingN-benzylpiperazine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A light beige solid is obtained, m.p. 259° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.38 (m, 4H); 2.50 (s, 4H)3.06 (d, 1H); 3.36 (s, 3H); 3.46 (s, 2H); 3.47 (d, 1H); 4.07 (q, 2H);5.29 (s, 2H); 5.46 (dd, 2H); 6.02 (s, 1H); 7.23-7.35 (m, 6H); 7.8 (d,1H); 8.35 (d, 1H).

NMR-C13 (DMSO): 8.40; 15.45; 36.47; 42.54; 50.7; 52.84; 53.13; 55.81;61.4; 62.14; 73.29; 99.57; 112.45; 122.61; 124.73; 127.05; 128.32;128.96; 138.45; 139.81; 1444.68; 152.63; 155.85; 159.15; 172.02.

IR(KBr): 1013; 1069; 1169; 1241; 1266; 1475; 1577; 1594; 1655; 1744.

EXAMPLE 5612-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., usingdimethylamine instead of N-methylpiperazine, then reduced according tothe method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A light beige solid is obtained, m.p. 184-190°C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H): 2.26 (s, 6H); 2.5 (s, 3H);3.05 (d, 1H); 3.48 (d, 1H); 3.98 (q, 2H); 5.28 (s, 2H); 5.46 (dd, 2H);6.06 (s, 1H); 7.37 (s, 1H); 7.84 (d, 1H); 8.35 (d, 1H).

NMR-C13 (DMSO): 8.45; 15.50; 36.52; 45.59; 50.62; 57.36; 61.43; 73.33,99.66; 112.29; 112.50; 122.67; 124.71; 126.99; 127.20; 127.44; 129.08;140.16; 144.80; 148.82; 152.71; 155.89; 159.22; 160.75; 172.07.

IR (KBr): 1448; 1595; 1653; 1749; 2950; 3438.

EXAMPLE 5712-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolone-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using diethylamineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A light beige solid is obtained. m.p.>270° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.04 (t, 6H); 1.86 (q, 2H); 2.50 (q, 2H);2.54 (s, 3H); 2.56 (q, 2H); 3.08 (d, 1H); 3.48 (d, 1H); 4.11 (q, 2H);5.25 (s, 2H); 5.46 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 7.80 (d, 1H);8.36 (d, 1H).

NMR-C13 (DMSO): 8.45; 11.68; 11.78; 15.43; 15.57; 36.5; 42.5; 46.68;46.83; 46.99; 50.77; 51.85; 52.08; 61.44; 73.30; 99.60; 112.18; 112.36;122.6; 124.6; 126.9; 127.1; 128.8; 141.45; 144.6; 148.6; 148.7; 152.65155.9; 159.1; 160.7; 163.2; 172.1.

IR (KBr): 1217; 1295; 1448; 1463; 1507; 1609; 1660; 1725; 2971; 3559.

Suspension of the above free base in absolute ethanol (50 ml/mmol)followed by treatment with ethanolic hydrogen chloride (2.5 N. 5 equ.)allows the corresponding hydrochloride to be obtained. Initially, ayellow solution forms, then a precipitate which is collected byfiltering after concentration to 40% of the initial volume, then washedwith ether. A vivid yellow solid is obtained, m.p. 269-272° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.34 (m, 1H); 1.86 (q, 2H); 2.56 (s, 3H);3.07 (d, 1H); 3.19 (m, 2H); 3.39 (m, 2H); 3.49 (d, 1H); 4.97 (m, 2H);5.41 (d, 1H); 5.54 (d, 1H); 5.58 (s, 2H); 6.08 (s, 1H); 7.42 (s, 1H);7.96 (d, 1H); 8.43 (d, 1H), 10.38 (s, 1H).

IR (KBr): 1039; 1070; 1226; 1282: 1509; 1654; 1724; 1744; 2921; 3409;3489.

EXAMPLE 585-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 1.00-0.80 (complex, 6H); 1.12 (q, 1H); 1.37 (s, 1H); 1.57(d, 3H); 1.85 (q, 2H); 2.13 (t, 2H); 2.82 (s, 1H); 2.85 (s, 1H); 3.05(d, 1H); 3.25 (s, 3H); 3.48 (d, 1H); 4.04 (q, 2H); 5.28 (s, 2H); 5.39(d, 1H); 5.52 (d, 1H); 6.03 (s, 1H); 7.36 (s, 1H); 7.82 (d, 1H); 8.40(d, 1H).

NMR-C13 (DMSO): 0.29; 8.43; 13.68; 15.48; 19.40; 21.93; 23.23; 30.39;34.20; 36.52; 42.55; 50.67; 53.84; 56.29; 57.67; 61.40; 73.32; 99.59;112.49; 122.62; 124.80; 127.18; 129.10; 140.31; 144.58; 148.64; 152.69;155.84; 159.19; 172.05.

IR (KBr) 1597; 1653; 1747; 3446.

EXAMPLE 595-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using pyrrolidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.72 (s, 4H); 1.85 (q, 2H); 2.57 (s, 4H);3.05 (d, 1H); 3.28 (s, 3H); 3.48 (d, 1H); 4.18 (q, 2H); 5.28 (s, 2H);5.39 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H); 7.36 (s, 1H); 7.82 (d, 1H);8.35 (d, 1H).

NMR-C13 (DMSO): 0.37; 8.47; 15.57; 23.48; 36.53; 42.61; 50.61; 53.45;54.09; 61.42; 73.33; 99.59; 112.37; 122.64; 124.51; 127.00; 127.25;128.63; 140.65; 144.77; 148.65; 152.73; 155.87; 159.20; 162.00; 167.00;172.07.

IR (Kflr): 1608; 1656; 1729; 3400.

EXAMPLE 6012-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., using1,2,3,6-tetrahydropyridine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p.>250° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.08 (s, 2H); 3.03 (s, 2H);3.05 (d, 1H); 3.28 (s, 3H); 3.48 (d, 1H); 4.12 (d, 1H); 5.28 (s, 2H);5.39 (d, 1H); 5.52 (d, 1H); 5.64 (d, 1H); 6.03 (s, 1H); 7.36 (s, 1H);7.83 (d, 1H); 8.36 (d, 1H).

NMR-C13 (DMSO): 8.45; 15.54; 25.84; 36.54; 42.55; 49.78; 50.68; 52.52;55.81; 61.42; 73.33; 99.62; 112.53; 122.66; 124.78; 125.03; 127.09;127.19; 131.73; 139.98; 144.76; 148.79; 152.73; 155.86; 159.19; 160.76;163.25; 172.07.

IR (KBr): 1605; 1656; 1733; 3451.

EXAMPLE 6112-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., usingdiisobutylamine instead of N-methylpiperazine, then reduced according tothe method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.75 (d, 12H); 0.87 (t, 3H); 1.83 (m, 4H); 2.15 (d, 1H);2.48 (s, 3H); 3.06 (d, 1H); 3.47 (d, 1H); 4.01 (q, 2H); 5.28 (s, 2H);5.39 (d, 1H); 5.53 (d, 1H); 6.03 (s, 1H); 7.37 (s, 1H); 7.83 (d, 1H);8.49 (d, 1H).

NMR-C13 (DMSO): 9.09; 16.14; 21.73; 26.57; 26.70; 37.15; 43.14; 51.05;55.49; 62.08; 64.74; 73.98; 100.42; 113.03; 123.38; 125.58; 127.12;127.32; 128.59; 130.27; 141.32; 145.51; 149.38; 149.51; 153.20; 156.62;159.86; 161.31; 163.79; 172.72.

IR (KBr): 1599; 1656; 1747; 2796; 3448.

EXAMPLE 625-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-fluoro-4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A light yellow solid isobtained, m.p. 274° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.15 (s, 3H); 2.31 (m, 4H);2.47 (m, 4H); 3.06 (d, 1H); 3.47 (d, 1H); 4.05 (m, 2H); 4.05 (s, 3H);5.28 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 7.87 (d, 1H);7.94 (d, 1H).

NMR-C13 (DMSO): 8.44; 36.53; 45.58; 45.95; 50.68; 52.86; 55.07; 56.20;56.47; 61.45; 73.32; 99.19; 105.90; 113.74; 113.91; 122.22; 125.60;129.46; 138.83; 144.51; 144.62; 144.94; 147.85; 147.98; 150.96; 152.82;155.34; 155.96; 159.19; 172.09.

IR (KBr): 1270; 1515; 1594; 1648; 1747; 2950; 3438.

EXAMPLE 635-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a, 30.b. and 30.c. is applied to3-fluoro-4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A light green solid is obtained, m.p.>275° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.42-1.50 (m, 6H); 1.84 (q, 2H); 2.50 (m,4H); 3.05 (d, 1H); 3.48 (d, 1H); 4.03 (s, 2H); 4.05 (s, 3H); 5.30 (s,2H); 5.45 (dd, 2H); 6.02 (s, 1H); 7.35 (s, 1H); 7.9 (d, 1H) 7.99 (d,1H).

NMR-C13 (DMSO): 8.44; 24.07; 25.9; 36.54; 42.57; 50.60; 54.26; 56.40;57.11; 61.42; 73.33; 99.17; 105.97; 113.75; 113.92; 122.21; 125.66;129.46; 139.23; 144.54; 144.98; 147.94; 151.0; 152.82; 155.34; 155.89;159.20; 172.07.

IR (KBr): 860; 1057; 1270; 1514; 1656; 1748; 2857; 2932; 3397.

Suspension of the above free base in absolute ethanol (50 ml/mmol)followed by treatment with ethanolic hydrogen chloride (2.5 N, 5 equ.)allows the corresponding hydrochloride to be obtained. Initially, ayellow solution forms, then a precipitate which is collected byfiltering after concentration to 40% of the initial volume, then washedwith ether. A light yellow solid is obtained, m.p. 264° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.42 (m, 1H); 1.70-1.85 (m, 7H); 3.06 (d,1H); 3.33 (m, 4H); 3.47 (m, 1H); 4.19 (s, 3H); 5.00 (s, 2H); 5.40 (d,1H); 5.54 (d, 1H); 5.61 (s, 2H); 6.02 (s, 1H); 7.37 (s, 1H); 7.95-8.04(m, 2H); 10.46(s, 1H).

NMR-C13 (DMSO): 9.12; 22.11; 22.91; 37.63; 43.20; 52.27; 53.20; 54.00;54.75; 57.91; 58.15; 62.12; 62.78; 73.97; 100.06; 106.96; 107.14;114.80; 123.20; 126.58; 130.48; 134.14; 145.33; 145.48; 149.49; 149.62;151.76; 153.84; 156.36; 156.69; 159.76; 172.73.

IR (KBr): 1010; 1072; 1240; 1271; 1469; 1511; 1574; 1598; 1648; 1734;2525; 2944; 3430; 3507.

EXAMPLE 649-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methoxyaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using dimethylamineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.84 (q, 2H); 2.29 (s, 6H); 3.06 (d, 1H);3.42 (d, 1H); 3.98 (q, 2H); 4.05 (s, 3H); 5.27 (s, 2H); 5.45 (s, 2H);5.95 (s, 1H); 7.32 (s, 1H); 7.82 (s, 1H); 8.19 (s, 1H).

NMR-C13 (DMSO): 8.41; 36.50; 42.55; 45.58; 50.62; 56.70; 57.42; 61.42;73.29; 99.28; 104.66; 122.34; 126.92; 127.55; 129.89; 130.04; 139.19144.20; 144.81; 151.08; 153.15; 155.91; 159.18; 172.04.

IR (KBr): 1048; 1242; 1482; 1611; 1659; 1730; 3301; 3417.

EXAMPLE 659-chloro-5-ethyl-5-hydroxy-10-methoxy12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to3-chloro-4-methoxyaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. The free base thus obtained is suspended in absolute ethanol(50 ml/mmol) then treated with ethanolic hydrogen chloride (2.5 N, 5equ.). Initially a yellow solution forms, then a precipitate which iscollected by filtering after concentration to 40% of initial volume, andwashed with ether. An orange solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.43 (q, 1H); 1.70 (d, 1H); 1.76 (m, 2H);1.86 (m, 4H); 3.07 (d, 1H); 3.28 (m, 2H); 3.47 (m, 3H); 4.20 (s, 3H);5.00 (q, 2H); 5.41 (d, 1H); 5.54 (d, 1H); 5.62 (s, 1H); 6.10 (s, 1H);7.36 (s, 1H); 7.88 (s, 1H); 8.31 (s, 1H).

NMR-C13 (CF₃COOD): 8.44; 22.11; 24.79; 38.27; 43.51; 54.28; 56.01;58.51; 58.75; 64.23; 77.59; 104.22; 110.49; 124.68; 129.44; 131.91;136.61; 140.01; 141.33; 144.72; 158.25; 161.10; 161.89; 178.85.

IR (KBr): 1079; 1288; 1488; 1562; 1578; 1648; 1747; 2936; 3406.

EXAMPLE 6612-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using1,2,3,6-tetrahydropyridine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. The free base thus obtained issuspended in absolute ethanol (50 ml/mmol) then treated with ethanolichydrogen chloride (2.5 N, 5 equ.). Initially a yellow solution forms,then a precipitate which is collected by filtering after concentrationto 40% of initial volume, and washed with ether. A yellow solid isobtained, m.p.>250° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 2.32 (m, 1H); 3.07 (d, 1H);3.48 (m, 3H); 3.89 (m, 8H); 4.06 (s, 3H); 5.08 (m, 2H); 5.40 (d, 1H);5.54 (d, 1H); 5.63 (q, 2H); 5.67 (d, 2H); 5.93 (d, 2H); 7.37 (s, 1H);7.59 (q, 1H); 7.79 (d, 1H); 8.14 (d, 1H); 10.80 (s, 1H).

NMR-C13 (DMSO): 8.47; 25.97; 36.40; 42.55; 49.75; 50.25; 50.61; 52.36;56.05; 61.44; 73.36; 98.95; 103.74; 121.99; 122.29; 124.98; 125.50;128.84; 129.84; 131.18; 138.47; 144.63; 145.18; 150.01; 155.93; 159.24;172.10.

IR (KBr): 827; 1065; 1228; 1289; 1592; 1653; 1746; 2363; 3373.

EXAMPLE 675-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>250° C.

NMR-1H (CF₃COOD): 1.17 (m, 6H); 1.62 (m, 2H); 1.89 (s, 1H); 2.07 (q,2H); 2.25 (m, 2H); 3.54 (m, 3H); 3.89 (d, 1H); 4.02 (s, 2H); 4.19 (s,3H); 7:94 (s, 1H); 8.10 (m, 1H); 8.29 (s, 1H); 8.50 (m, 1H).

NMR-C13 (CF₃COOD): 8.43; 13.79; 17.43; 20.89; 30.01; 32.85: 38.26;43.50; 54.13; 56.09; 57.87; 58.27; 64.22; 77.57; 107.37; 110.56; 125.75129.36; 129.42; 132.78; 136.04; 136.65; 139.91; 140.38; 144.31; 158.30;161.94; 164.90; 178.84.

IR (KBr): 825; 1056; 1230; 1260; 1516; 1641; 1655; 1736; 2921; 3395.

EXAMPLE 685-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. 215-219° C.

NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (m, 2H); 2.15 (s, 3H); 2.35 (m, 4H);2.5 (m, 4H); 3.25 (dd, 2H); 3.95 (s, 3H); 4.05 (s, 2H); 5.3 (s, 2H);5.45 (dd, 2H); 6 (s, 1H); 7.3 (s, 1H); 7.5 (d, 1H); 7.7 (s, 1H); 8.05(d, 1H).

NMR-C13 (DMSO): 9.12; 14.36; 20.08; 23.93; 46.61; 51.35; 53.58; 55.71;56.34; 56.73; 58.37; 62.11; 74.03; 99.62; 104.49; 122.66; 123.11;129.54; 130.53; 131.82; 139.05; 145.3: 145.86: 150.67; 156.62; 158.71;159.91; 172.77.

IR (KBr): 1590; 1624; 1655; 1744; 2801; 2935; 3423.

EXAMPLE 695-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using pyrrolidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.85 (t, 3H); 1.7 (s, 4H); 1.85 (q, 2H); 2.55 (s, 4H);3.25 (dd, 2H); 3.9 (s, 3H); 4.15 (s, 2H); 5.25 (s, 2H): 5.45 (dd, 2H); 6(s, 1H); 7.35 (s, 1H); 7.5 (d, 1H); 7.7 (s, 1H); 8.05 (d, 1H).

NMR-C13 (DMSO): 9.68; 24.74; 51.8; 54.71; 55.25; 56.3; 56.87; 62.3;62.64; 74.5; 100.14; 104.8; 104.92; 123.19; 123.45; 129.79; 130.49;132.32; 132.50; 140.5; 145.83; 146.4; 151.27; 157.15; 159.25; 160.45;173.3.

IR (KBr): 1255; 1516; 1535; 1613; 1655; 1735; 3438; 3762; 3830.

EXAMPLE 7012-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Examples 30.a., 30.b. and 30.c. is applied to4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., usingN-benzylpiperazine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A beige, solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.45 (s, 2H); 2.4 (m, 4H);2.55 (m, 4H); 3.25(dd, 2H); 3.45 (s, 2H); 3.95 (s, 3H); 4.05 (s, 2H);5.3 (s, 2H); 5.45 (dd, 2H); 6 (s, 1H); 7.3 (m, 6H); 7.5 (d, 1H); 7.75(s, 1H); 8 (d, 1H).

NMR-C13 (DMSO): 7.38; 49.56; 51.89; 54.46; 54.82; 54.98; 55.1; 60.1;60.35; 61.11; 72.26; 97.86; 102.6; 102.76; 120.9; 121; 121.2; 121.4;126; 127.25; 127.77; 127.88; 128.76; 130.13; 130.2; 137.25; 137.36;143.53 144.08; 148.86; 156.86; 156.95; 158.15; 171.02.

IR (KBr): 1235; 1259; 1517; 1586; 1614; 1654; 1747; 2927; 3450; 3762;3848.

Suspension of the above free base in absolute ethanol (50 ml/mmol)followed by treatment with ethanolic hydrogen chloride (2.5 N, 5 equ.)allows the corresponding hydrochloride to be obtained. Initially, ayellow solution forms, then a precipitate which is collected byfiltering after concentration to 40% of the initial volume, then washedwith ether. A yellow solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 2.5 (s, 2H); 2.65 (m, 2H); 3(m, 2H); 3.2 (m, 2H); 3.35 (dd, 2H); 3.35 (s, 2H); 3.95 (s, 3H); 4.15(s, 2H); 4.3 (s, (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H); 7.3 (s, 1H); 7.4(s, 2H); 7.55 (m, 2H); 7.7 (s, 1); 8.05 (d, 1H); 10.45 (s, 1H).

IR (KBr): 1207; 1233; 1439; 1449; 1458; 1508; 1610; 1620; 1655; 1727;3398.

EXAMPLE 719-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline3,15-dione

The procedure described in Examples 30.a, 30.b. and 30.c. is applied to3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>275° C.

NMR-1H (DMSO): 0.86 (m, 6H); 1.15 (m, 2H); 1.37 (m, 1H); 1.60 (m, 2H);1.80 (m, 2H); 2.10 (m, 2H); 2.60 (s, 3H); 2.80 (m, 2H); 3.05 (d, 1H);3.48 (d, 1H); 4.02 (s, 2H); 5.30 (s, 2H); 5.45 (dd, 2H); 6.02 (s, 1H);7.40 (s, 1H); 8.20 (s, 1H); 8.40 (s, 1H).

NMR-C13 (DMSO): 9.10; 21.28; 22.61; 31.07; 34.89; 37.18; 43.22; 54.5356.83; 62.10; 73.94; 80.06; 100.43; 123.41; 127.08; 129.11; 130.58;135.88; 136.89; 141.00; 145.28; 148.49; 153.51; 156.60; 159.85; 172.77;174.05.

IR (KBr): 1605; 1657; 1734; 3342.

EXAMPLE 7210-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The procedure described in Stage 11.i. is applied to3-fluoro-4-methoxy-acetanilide in order to produce2-chloro-7-fluoro-6-methoxy-3-quinolinecarbaldehyde which is treatedwith an excess of boron tribromide in dichloromethane at ambienttemperature for 24 hours.2chloro-7-fluoro-6hydroxy-3-quinolinecarbaldehyde is obtained; which isO-benzylated in dimethylformamide in the presence of benzyl bromide andof potassium carbonate in order to produce6-(benzyloxy)-2-chloro-7-fluoro-3-quinolinecarbaldehyde, which isreduced with sodium borohydride in methanol in order to produce thecorresponding quinolinemethanol. The latter is coupled with compound (M)as described in Stage 11.j. of Example 11. The resultant coupled productis cyclized according to the procedure of Stage 11.k. A yellow solid isobtained, m.p.>275° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 5.25 (s, 2H);5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.4-7.6 (m, 5H); 7.88 (d,1H); 7.95 (d, 1H); 8.56 (s, 1H).

EXAMPLE 735-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

The hydrogenolysis procedure of Example 14 is applied to the compound ofExample 72. A yellow solid is obtained, m.p.>275° C.

NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 5.25 (s, 2H);5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.8 (d, 1H); 7.90 (d, 1H);8.56 (s, 1H).

EXAMPLE 745-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl2-aminoacetate hydrochloride

74a.5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl2-[(tert-butoxycarbonyl)amino]acetate

A mixture of5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(200 mg, 0.526 mmol, example 18), N-Boc-glycine (185 mg, 1.051 mmol) anda catalytic quantity of 4-dimethylaminopyridine (20 mg) in anhydrouspyridine (10 ml) is treated at 0° C. and under argon withdicyclohexylcarbodiimide (239 mg, 1.16 mmol), then agitated at ambienttemperature for 48 hours. The volatiles are driven off under vacuum andthe residue is chromatographed (SiO₂, 1% methanol in chloroform) inorder to produce the desired intermediate (40 mg, 14%), a yellow solid.

NMR-1H (CDCl₃): 1.20 (t, 3H); 1.38 (s, 9H); 1.40-1.70 (m, 2H); 3.10 (d,1H); 4.00 (d, 2H); 4.30 (d, 1H); 5.00 (t, 1H); 5.20 (s, 2H); 5.30-5.90(dd, 2H); 7.20 (s, 1H); 7.50-8.10 (m, 2H); 8.30 (s, 1H).

74b.5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl2-aminoacetate hydrochloride

The intermediate obtained above (40 mg, 0.072 mmol) in solution indichloromethane (10 ml) is maintained at 0° C. and dioxan saturated withhydrogen chloride (8 ml) is added dropwise. The yellow suspension thusformed is maintained under agitation for 2 hours, then the volatiles aredriven off under vacuum. The residue, taken up in water (5 ml), iswashed with dichloromethane (3×30 ml). The aqueous phase is frozen andlyophilized in order to produce the expected salt, a hygroscopic yellowsolid (20 mg, 50%).

NMR-1H (CDCl₃): 1.00 (t, 3H), 2.15 (m, 1 H); 2.30 (m, 1H): 3.60 (d, 1H);3.90 (d, 1H); 4.15 (s, 2H); 5.10 (s, 2H); 5.40 (d, 1H); 5.70 (d, 2H);7.40 (s, 1H); 7.80 (m, 2H); 8.50 (s, 1H).

EXAMPLE 755-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl3-aminopropanoate

The procedure of Example 74 is applied to5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneusing N-Boc-β-alanine instead of N-Boc-glycine, then the Boc protectorof the intermediate thus obtained is cleaved by treatment withtrifluoroacetic acid in dichloromethane. The volatiles are evaporatedoff under vacuum and the residue is taken up in dichloromethane. Theresultant solution is washed with dilute bicarbonate, dried andevaporated. A yellow solid is obtained.

By applying the method of Examples 74 and 75 to other compounds, forexample to those disclosed in the present application, similar resultsare obtained. In this way an entire class of campothecin analogues isaccessible in “prodrug” form

EXAMPLE 762,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(84 mg, example 14) in acetic acid (2.5 ml) is treated with1,3,5-triethylhexahydrotriazine (0.5 ml). The reaction mixture isagitated at 70° C. for 30 minutes, then evaporated under vacuum. Theresidue is taken up in ethanol, filtered and washed with ether. A solidis obtained, m.p.>275° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.50 (t, 3H); 1.85 (q, 2H); 2.77 (q, 2H);3.05 (d, 1H); 3.47 (d, 1H); 4.37 (s, 2H); 5.00 (s, 2H); 5.22 (s, 2H);5.45 (dd, 2H); 6.00 (s, 1H); 7.34 (s, 1H); 7.36 (d, 1H); 7.93 (d, 1H);8.53 (s, 1H).

NMR-C13 (DMSO): 8.46; 13.48; 36.46; 42.49; 45.49; 46.44; 50.75; 61.43;73.33; 82.06; 99.02; 112.90; 122.00; 122.98; 125.42; 127.04; 129.04;130.20; 144.09; 144.97; 149.87; 152.92; 155.98; 172.07.

IR (KBr): 1045; 1215; 1502; 1604; 1657, 1722.

EXAMPLE 779-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(200 mg, example 14) in acetic acid (5 ml) is treated withhexahydro-1,3,5-trimethyltriazine (110 mg). The reaction mixture isagitated at 70° C. for 30 minutes, then evaporated under vacuum. Theresidue is taken up in ethanol, filtered and washed with ether. A solidis obtained, m.p.>275° C.

NMR-1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 3.04 (d, 1H); 3.48 (d, 1H);4.33 (s, 2H); 4.93 (s, 2H); 5.28 (s, 2H); 5.45 (dd, 2H); 6.01 (s, 1H);7.35 (s, 1H); 7.38 (d, 1H); 7.94 (d, 1H); 8.49 (s, 1H).

NMR-C13 (DMSO): 8.46; 36.43; 37.85; 42.55; 48.68; 50.79; 61.43; 73.35;83.82; 99.04; 112.49; 122.04; 123.00; 125.46; 127.14; 129.07; 130.27;144.99; 149.95; 152.46; 155.99; 172.09

IR (KBr): 1047; 1058; 1219; 1246; 1295, 1439; 1504; 1604, 1655, 1735.

EXAMPLE 782-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(200 mg, example 14) in acetic acid (5 ml) is treated with1,3,5-tribenzylhexahydrotriazine (285 mg). The reaction mixture isagitated at 70° C. for 30 minutes, then evaporated under vacuum. Theresidue is taken up in ethanol, filtered and washed with ether. A solidis obtained, m.p.>275° C.

NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 3.47 (d, 1H);3.96 (s, 2H); 4.33 (s, 2H); 5.04 (s, 2H); 5.17 (s, 2H); 5.44 (dd, 2H);6.01 (s, 1H); 7,38 (m, 6H); 7.42 (d, 1H); 7.97 (d, 1H); 8.42 (s, 1H).

NMR-C13 (DMSO): 8.42; 19.96; 36.45; 42.51; 46.36; 50.78; 55.38; 61.39;73.31; 99.00; 112.55; 122.01; 123.08; 125.38; 127.09; 127.47; 128.70;129.14; 130.35; 128.40; 139.19; 144.18; 149.99; 152.84; 155.92; 159.24;172.05.

IR (KBr): 1056; 1205; 1225; 1248; 1504; 1535; 1599; 1655; 1726.

EXAMPLE 792-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

A suspension of5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15 (4H,13H)-dione (200 mg, example 73) in acetic acid(5 ml) is treated with 1,3,5-tribenzylhexahydrotriazine (285 mg). Thereaction mixture is agitated at 70° C. for 30 minutes, then evaporatedunder vacuum. The residue is taken up in ethanol, filtered and washedwith ether. A solid is obtained, m.p.>250° C.

NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 3.48 (d, 1H);3.95 (s, 2H): 4.45 (s, 2H); 5.20 (s, 4H); 5.45 (dd, 2H); 6.05 (s, 1H);7.40 (s, 7H); 7.90 (d, 1H); 8.45 (s, 1H).

IR (KBr): 1248; 1451; 15001; 1598; 1657; 1727.

EXAMPLE 80(+)-5-Ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione[(+)-EHHOPD]

80.a. Quinidine salt of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid:

Tertiobutyl3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoate (40 g;100 mmol) is treated with trifluoroacetic acid (150 ml) and the reactionmedium is agitated for 18 hours at 20° C. After evaporation of thetrifluoroacetic acid, methylene chloride (200 ml) is poured in and asaturated solution of sodium bicarbonate is introduced until thepH=7.5-8. After decantation, the aqueous phase is washed with 100 ml ofmethylene chloride. The pH of the aqueous phase is then adjusted to 1 bythe addition of a solution of 6N hydrochloric acid. The product is thenextracted from the aqueous phase with methylene chloride (2 times 200ml). The solution is dried over magnesium sulphate and concentrated. The3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid (31.1g; 90 mmol) thus obtained, taken up in isopropyl alcohol (30 ml), istreated with a solution of quinidine (29.2 g; 90 mmol) in isopropylalcohol (30 ml) at 50° C. under agitation until complete dissolution.Then the reaction medium is left so that temperature reduces to 40° C.,the agitation is stopped and the temperature allowed to drop to 20° C.The medium is taken to 0° C. without agitation then maintained at thistemperature for 16 hours. Then the temperature is allowed to rise to 20°C. and agitation is carried out until crystallization. The medium isdiluted with isopropyl alcohol then filtered The precipitate is rinsedwith isopropyl alcohol. The salt of the (+) enantiomer precipitates(m=26.6 g) while the salt of the (−) enantiomer remains in solution inthe isopropyl alcohol. Thus the filtrate is recovered which isconcentrated in order to produce an oil (34 g) which is used withoutother purification in the following stage.

The products are analyzed by HPLC on a 51μ CHIRAL AGP column (10 cm×4mm) eluted with a 30/920/50 isopropyl alcohol/water/phosphate buffermixture, pH=6.5, at a flow rate of 1.2 ml/min, UV detection at 280 nm.The retention times obtained are 6.4 minutes for the (−) enantiomer and2.8 minutes for the (+) enantiomer. The (−) enantiomer/(+) enantiomerratio is 83/17.

80.b. (−)-3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoicacid

The solution in isopropyl alcohol of the quinidine salt of the (−)enantiomer of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid(Stage 80.a) is concentrated. The concentrate is taken up in 270 ml ofmethylene chloride and 270 ml of a 1N solution of hydrochloric acid. Thereaction medium is agitated for 16 hours at 20° C. After decantation,the organic phase is concentrated, the concentrate is taken up inmethanol in order to be used in the following stage.

13.5 g of product (yield of 87%) and a (−)enantiomer/(+) enantiomerproportion of 85/15 are obtained.

The HPLC retention times (same protocol as in 1.a.) are:

(−) enantiomer: 6.4 minutes

(+) enantiomer: 2.8 minutes

80.c.(+)-5-Ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione:

(−)-3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid(13.5 g; 39 mmol; Stage 80.b) is put in solution in 87 ml of methanol.This solution is poured under nitrogen onto 10% Palladium on damp carbonat 50% (27.7 g; 13 mmol). The reaction medium is agitated for 5 minutes,then it is poured into a solution of ammonium formate (11.5 g; 183 mmol)in 135 ml of methanol. The reaction medium is agitated for 30 minuteswhile allowing the temperature to rise, then it is heated at 40° C. for30 minutes. The medium is then filtered on a bed of Clarcel followed byconcentrating, 40 ml of toluene is poured in which is evaporated off;this operation is repeated in order to eliminate the methanol. Theresidue thus obtained is taken up in 45 ml of THF. Then a solution ofdicyclohexylcarbodiimide (7.180 g; 34.5 mmol) in 20 ml of THF is thenpoured in. The reaction medium is heated to 50° C. for 1 hour. Themixture is taken to 20° C. then the dicyclohexylurea is filtered. Thefiltrate is concentrated to dryness. The residue is put in solution in46 ml of acetonitrile, 6.0 g (40.5 mmol.) of sodium iodide then 5.13 ml(40.5 mmol) of trimethylsilyl chloride are added. The reaction medium ismaintained under agitation at ambient temperature for 5 hours. Then 28ml of acetonitrile and 5.6 ml of water are added. The precipitateobtained is filtered then taken up in 1 ml of water, and the pH isadjusted to 7.5 by the addition of a solution of ammonium hydroxide. Thesolid obtained is filtered and dried. M=4.2 g of final product isobtained with a yield of 34% and a (+) enantiomer/(−) enantiomerproportion of 88.4/11.6.

HPLC analysis is carried out on a Chiralcel OD column 25 cm×4.6 mm theeluants used are heptane 600 and ethanol 400, the flow rate is 1 ml/min210 nm. The retention times obtained are

(−) enantiomer 7.1 minutes

(+) enantiomer: 9 minutes.

The product is taken up in acetone (40 ml), then water (150 ml) isadded. The reaction is left to precipitate and 3 g of product isobtained with a (+) enantiomer/(−) enantiomer proportion of 99.4/0.6.

NMR ¹H (250 MHz, DMSO D6): 0.8 (t, 3H, CH₃—CH₂); 1.65 (m, 2H, CH₂—CH₃);3.00-3.35 (q, 1H+1H, —CH₂—C═O); 5.3 (q, 2H, CH₂—O); 5.7 (s, —OH); 6.35(d, aromatic 1H); 7.3 (d, aromatic 1H); 11.7 (s, N—H).

EXAMPLE 81(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

81.a. N-(3,4-difluorophenyl)acetamide:

A mixture of 3,4-difluoroaniline (50 ml; 0.5 mole) and triethylamine (70ml; 0.5 mol) in dichloromethane (1.5 l) is cooled down using an icebath. Acetic anhydride (71.5 ml; 0.75 mol) is added dropwise and thereaction mixture is then agitated for 1 hour at ambient temperature. Themixture obtained is then washed successively with water, a 10% solutionof sodium bicarbonate and saturated salt water. The organic fraction isdried over sodium sulphate and concentrated under reduced pressure. Theresidue is suspended in pentane, filtered and dried under reducedpressure in order to produce the product in the title (78 g; 91% yield)in the form of a whitish solid (M.p. 126-127.5° C.).

NMR ¹H (DMSO): 2.15 (s, 3H); 7.10-7.65 (m, 2H); 7.65-8.10 (m, 1H); 10.30(wide peak. 1H).

81.b. 2-chloro-6,7-difluoro-3-quinoline-3-carbaldehyde:

The general procedure described by Meth-Cohn et al., J. Chem. Soc.Perkin Trans. I, 1981, 1520 and 2509 is used.

The product of Stage 81.a (32 g; 220 mmol) is added to a Vilsmeyerreagent, obtained by the dropwise addition under an argon atmosphere ofphosphorus oxychloride (103 ml; 1.1 mol) in anhydrous DMF (34 ml; 440mmol) cooled down in an ice bath and agitated for 30 minutes beforeleaving the temperature to rise to ambient temperature. The mixture thusobtained is agitated at 70° C. for 16 hours. After returning thereaction medium to ambient temperature, it is added dropwise to awater-ice mixture (400 ml) and agitated for 2 hours. The precipitateobtained is filtered and washed with water, then dried in order toproduce the product in the title (9 g; 18% yield) in the form of ayellow solid (M.p. 226.5-229° C.).

NMR ¹H (DMSO): 8.17 (dd, 1H); 8.39 (dd, 1H); 8.97 (d, 1H); 10.34 (d,1H).

IR (KBr): 888, 1061, 1262, 1507, 1691 cm⁻¹.

81.c. 2-chloro-6,7-difluoro-3-quinolylmethanol:

A suspension of the product of Stage 81.b (9 g; 39 mmol) in methanol(400 ml) is treated with sodium borohydride (2 g; 53 mmol) at ambienttemperature for half an hour. The excess borohydride is destroyed withacetic acid (2 nm). The volatile substances are eliminated under reducedpressure. The residue is dissolved in ethyl acetate (500 ml), themixture obtained then being washed successively with a dilute solutionof sodium bicarbonate, water and saturated salt water, followed bydrying over magnesium sulphate and concentration under reduced pressure.The residue is recrystallized from 1,2-dichloroethane in order toproduce the product in the title (8 g; 80% yield) in the form of a beigesolid (M.p. 166.5-167° C.).

NMR ¹H (DMSO): 4.67 (d, 2H); 5.80 (t, 1H); 8.01 (dd, 1H); 8.22 (dd, 1H);8.48 (s, 1H).

IR (KBr): 871, 1038, 1253, 1513 cm⁻¹.

81.d.(+)-8-(2-chloro-6,7-difluoro-3-quinolinemethanol)-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridine-3,9-dione:

Diethylazodicarboxylate (1.24 ml; 7.87 mmol) is added dropwise atambient temperature and under an argon atmosphere to a solution inanhydrous DMF (30 ml) of (+)-EHHOPD (1.58 g; 7.08 mmol; Stage 80.c.),the product of Stage 81.c (1.62 g; 7.06 mmol) and tributylphosphine(1.91 ml; 7.87 mmol). The mixture thus obtained is then agitated for 16hours. The reaction medium is then evaporated to dryness under reducedpressure. The residue is purified by chromatography on a silica column(eluant:ethyl acetate). The solid obtained is taken up in diethylether,filtered and dried in order to produce the product in the title (1.56 g;51% yield) in the form of a whitish solid (M.p. 196° C.).

NMR ¹H (DMSO): 0.84 (t, 3H); 1.74 (m, 2H): 3.02 (d, 1H); 3.34 (d, 1H);5.29 (s, 2H); 5.31 (dd, 2H); 5.75 (s, 1H); 6.51 (d, 1H); 7.80 (d, 1H);8.03 (dd, 1H); 8.07 (s, 1H); 8.17 (dd, 1H).

IR (KBr): 875, 1057, 1360, 1507, 1574, 1647, 1749 cm⁻¹.

81.e.(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione:

A mixture of the product of Stage 81.d (1.53 g; 3.52 mmol; Stage 2.d.),tetrabutylammonium bromide (1.25 g; 3.87 mmol), potassium acetate (520mg; 5.28 mmol), triphenylphosphine (180 mg; 0.70 mmol) and palladium(II) acetate (79 mg; 0,35 mmol) is agitated under an argon atmosphere inanhydrous acetonitrile heated at reflux for 22 hours. After the reactionmedium has returned to ambient temperature, concentration under reducedpressure is carried out before chromatography on a silica column (eluantCH₂Cl₂/MeOH mixture 98/2). The product in the title is then obtained(960 mg; yield 68%; purity determined by HPLC: 97.1%). This product istaken up in anhydrous CH₂Cl₂ (100 ml) and agitation is carried out for24 hours, followed by filtering and drying under reduced pressure inorder to produce the purified product of the title (850 mg; yield 61%;purity determined by HPLC: 99.6%) in the form of a white solid.

NMR ¹H (DMSO): 0.87 (t, 3H); 1.85 (m, 2H); 3.08 (d, 1H); 3.44 (d, 1H);5.26 (s, 2H); 5.39 (d, 2H); 5.52 (d, 2H); 5.99 (wide peak, 1H); 7.39 (s,1H); 8.15 (dd, 1H); 8.23 (dd, 1H); 8.68 (s, 1H).

IR (KBr): 871, 1261, 1512, 1579, 1654, 1746 cm⁻¹.

EXAMPLE 82(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridiniumchloride

82.a. 1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-ethanone:

3-chloro-4-methylaniline (44.4 ml; 0.366 mol) in 1,2-dichloroethane (440ml), under an argon atmosphere, is cooled down in an ice bath Thefollowing are added dropwise and in the order of this mixture: borontrichloride (1M in heptane; 400 ml; 0.4 mol), chloroacetonitrile (28 ml;0.44 mol) and diethylaluminium chloride (1M in heptane; 400 ml; 0.4mol). For the addition, the temperature is maintained below 20° C. Theresultant mixture is then heated at reflux for 3 hours, then cooled downto 10° C. The hydrolysis of the reaction medium is then carried outcautiously using 2N hydrochloric acid (240 ml) and it is heated atreflux for 1 hour. Water (1 l) and ethyl acetate (1 l) are added, themixture obtained is agitated for 15 minutes before separating thephases. The aqueous phase is again extracted with ethyl acetate (200ml), and the combined organic phases are washed with water (500 ml).After drying over magnesium sulphate the organic phase is concentrated.The residue is taken up in petroleum ether (fraction having a boilingpoint of 45 to 60° C.; 150 ml) and the mixture thus obtained is left for16 hours at 4° C. The resultant precipitate is collected by filtration,washed with petroleum ether and dried under reduced pressure in order toproduce the product in the title (25 g; 31% yield). M.p. 129-130° C.

NMR ¹H (DMSO): 2.20 (s, 3H); 4.98 (s, 2H); 6.90 (s, 1H); 7.15 (widepeak, 2H); 7.70 (s, 1H).

IR (KBr): 871, 1018, 1183, 1225, 1270, 1533, 1577, 1619, 1662 cm⁻¹.

82.b. Ethyl7-chloro-4-chloromethyl-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate:

The product of Stage 82.a (25 g; 0.11 mol) and triethylamine (30.6 ml;0.22 mol) are mixed together in acetonitrile (526 ml). Ethylmalonylchloride (28.1 ml; 0.22 mol) is added at ambient temperature and underan argon atmosphere. The mixture obtained is agitated for 3 hours.Sodium ethanolate (prepared by the dissolution of 3 g, i.e. 0.13 mol, ofsodium in 140 ml of absolute ethanol) is then added dropwise and theresultant mixture is agitated at ambient temperature for 16 hours. Theprecipitate is collected by filtration, washed successively withethanol, water, ethanol and ether. It is then dried under reducedpressure at 70° C. over phosphorus pentoxide in order to produce theproduct in the title (28.6 g; 83% yield) in the form of a whitishpowder.

NMR ¹H (DMSO): 1.30 (t, 3H); 2.40 (s, 3H); 4.35 (q, 2H); 4.85 (s, 2H);7.41 (s, 1H); 7.91 (s, 1H); 12.15 (wide peak, 1H).

IR (KBr): 879, 1108, 1250, 1288, 1483, 1664, 1721 cm⁻¹.

82.c. Ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate:

The product of Stage 82.b (28.4 g; 90 mmol) is heated for 4 hours atreflux in phosphorus oxychloride (400 ml). The mixture obtained isconcentrated under reduced pressure (20 mm Hg) at 80° C. The residue istaken up in diisopropylether (400 ml). The resultant precipitate iscollected by filtration, washed with ether and petroleum ether, thendried under reduced pressure in order to produce the product in thetitle (25.4 g; 85% yield) in the form of a whitish powder (M.p. 126-127°C.).

NMR ¹H (DMSO): 1.37 (t, 3H); 2.58 (s, 3H); 4.49 (q, 2H); 5.14 (s, 2H);8.16 (s, 1H); 8.35 (s, 1H).

IR (KBr): 874, 1006, 1163, 1243, 1278, 1577, 1723 cm⁻¹.

82.d. 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolylmethanol:

The product of Stage 82.c (25.2 g; 76.5 mmol) is mixed under an argonatmosphere with dichloroethane (630 ml). Diisobutylaluminium hydride (1Min dichloromethane; 307 ml; 307 mmol) is added dropwise while thereaction mixture is agitated and the temperature is maintained below 20°C. The reaction mixture is then agitated at ambient temperature for 3hours, then poured into an aqueous solution of potassium tartrate(concentrated to 20% by weight; 1.5 l). The emulsion thus obtained isagitated vigorously for 1 hour, filtered on celite and the two phasesare then separated. The aqueous phase is extracted with ethyl acetate(200 ml) and the combined organic phases are washed with an aqueoussolution of sodium chloride (concentrated to 20% by weight; 500 ml). Theorganic phase obtained is dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The residue is taken up indiethylether (50 ml) and the resultant precipitate is collected byfiltration. By drying under reduced pressure, the product in the titleis obtained (18.3 g; 93% yield) in the form of a whitish powder (M.p.169-170° C.).

NMR ¹H (DMSO): 2.57 (t, 3H); 4.84 (s, 2H); 5.36 (s, 2H); 8.06 (s, 1H);8.27 (s, 1H).

IR (KBr): 870, 1022, 1102, 1304, 1482, 1567 cm⁻¹.

82.e.2,7-dichloro-6-methyl-4-(4-methylpiperidinomethyl)-3-quinolylmethanol:

A solution of the product of Stage 82.d (16.2 g; 55.7 mmol) in THF (70ml) is treated with a solution of 4-methylpiperidine (23 ml; 195 mmol).The mixture obtained is agitated at ambient temperature for 2 hours.Water (200 ml) and dichloroethane (200 ml) are added. The organic phaseis washed with an aqueous solution of sodium chloride (concentrated to20% by weight; 100 ml), dried over magnesium sulphate and concentratedunder reduced pressure. By crystallization of the residue fromdiethylether, the product in the title is obtained (18.3 g; 93% yield)in the form of a white crystalline solid (M.p. 170-171,5° C.).

NMR ¹H (CDCl₃): 0.88 (d, 3H); 1.17 (m, 2H); 1.42 (m, 1H); 1.60 (m, 2H);2.19 (t, 2H); 2.56 (s, 3H); 2.82 (d, 2H); 4.02 (s, 2H); 4.93 (s, 2H);6.36 (wide peak, 1H); 7.95 (s, 1H); 8.02 (s, 1H).

IR (KBr): 971, 1013, 1105, 1293, 1479, 1559 cm⁻¹.

82.f.(+)-8-[2,7-dichloro-6-methyl-4-(4-methylpiperidinomethyl)-3-quinolylmethyl]-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pydidine-3,9-dione:

A suspension of (+)-EHHOPD (obtained in Stage 80.c.; 1.56 g; 7,0 mmol)in anhydrous dioxane (70 ml) is treated successively, under an argonatmosphere, with the product of Stage 82.e (2.47 g; 7.0 mmol),triphenylphosphine (2.02 g; 7.7 mmol) and diisopropyl azodicarboxylate(1.07 ml; 10.5 mmol). The mixture is agitated at ambient temperature for16 hours. The volatile substances are then evaporated off under reducedpressure. The residue is purified by chromatography on a silica column(eluant: ethyl acetate). The solid obtained is taken up in diethylether,filtered and dried in order to produce the product in the title (1.96 g;50% yield) in the form of a whitish solid (M.p. 182° C.).

NMR ¹H (DMSO): 0.89 (m, 8H); 1.23 (m, 1H); 1.41 (t, 2H); 1.64 (m, 2H);2.09 (q, 2H); 2.59 (m, 5H); 3.15 (dd, 2H); 4.06 (dd, 2H); 5.31 (dd, 2H);5.35 (dd, 2H); 5.75 (s, 1H); 6.29 (d, 1H); 7.17 (d, 1H); 8.06 (s, 1H);8.46 (s, 1H).

IR (KBr): 878, 1053, 1275, 1474, 1572, 1648; 1747 cm⁻¹.

82.g.(+)-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-c]quinoline-3,15-dione:

A mixture of the product of Stage 82.f (3.80 g; 6.80 mmol),tetrabutylammonium bromide (2.42 g; 7.5 mmol), potassium acetate (1.00g; 10.2 mmol), triphenylphosphine (890 mg; 3.4 mmol) and palladium (II)acetate (220 mg; 0,68 mmol) is agitated under an argon atmosphere inanhydrous acetonitrile (85 mg) at reflux for 24 hours. After coolingdown to ambient temperature, the resultant precipitate is collected byfiltration and washed successively with acetonitrile, water, acetone anddiethylether in order to produce, after drying under reduced pressure,the product in the title (2.5 g; 70% yield) in the form of a whitishpowder.

NMR ¹H (DMSO): 0.86 (m, 6H); 1.12 (q, 2H); 1.36 (m, 1H); 1.56 (d, 2H);1.84 (q, 2H); 2.12 (t, 2H); 2.56 (s, 3H); 2.83 (dd, 2H); 3.26 (dd, 2H);4.03 (dd, 2H); 5.28 (dd, 2H); 5.45 (dd, 2H); 6.04 (s, 1H); 7.34 (s, 1H);8.14 (s, 1H); 8.38 (s, 1H).

IR (KBr): 870, 1058, 1208, 1280, 1477, 1593, 1655, 1749 cm⁻¹.

82.h. (+)1-[(5R)-9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-c]quinolin-12-ylmethyl]-4-methyl-hexahydropyridiniumchloride:

A mixture of the product of Stage 82.g (2.3 g; 7.7 mmol) and absoluteethanol (300 ml) is subjected to ultrasound for 2 minutes. The milkysuspension obtained is agitated and treated with hydrochloric acid (1Nsolution; 13.2 ml; 13.2 mmol) in order to produce a light yellowsolution which, at rest, forms a gel-type precipitate. The precipitateis collected by filtration on a BŸchner and washed successively withethanol and ether, then dried under reduced pressure in order to producethe product in the title (2.1 g; 85% yield).

NMR ¹H (DMSO): 0.87 (m, 6H); 1.59 (m, 5H); 1.84 (q, 2H); 2.64 (s, 3H);3.28 (dd, 2H); 3.45 (s, 2H); 4.93 (s, 2H); 5.47 (dd, 2H); 5.61 (s, 2H);6.04 (wide peak, 1H); 7.41 (s, 1H); 8.28 (s, 1H); 8.63 (s, 1H); 10.30(wide peak, 1H).

IR (KBr): 1043, 1212, 1479, 1585, 1655, 1751 cm⁻¹.

Pharmacological Study of the Products According to the Invention

1. Relaxation Activity Test of DNA Induced by Topoisomerase 1

All the reactions are carried out in a 20 μl reaction buffer constitutedby 50 mM of Tris-HCl (pH 7.5), 50 mM of KCl, 0.5 mM of dithiothreitol,10 mM of MgCl₂, 0.1 mM of ethyldiamine tetraacetic acid (EDTA), 30 μg/mlof bovine serum albumin and 300 ng of supercoiled pUC19 (PharmaciaBiotech, Orsay, France) with or without the compounds to be tested atdefined concentrations. All the compounds to be tested are initiallydissolved in dimethylsulphoxide (DMSO) at 50 mM, the other dilutionsbeing carried out with distilled water. The final concentration of DMSOdoes not exceed 1% (v/v). The reaction is initiated by the addition of aunit of DNA topoisomerase 1 of purified calf thymus (Gibco-BRL, Paisley,United Kingdom) and is carried out for 15 minutes at 37° C. Thereactions are stopped by the addition of 3 μl of a mixture containing 1%dodecyl sodium sulphate at 1%, 20 mM of EDTA and 500 μg/ml of Kproteinase (Boehringer Mannheim, Meylan, France). After an additionalincubation period of 30 minutes at 370° C., 2 μl of a loading buffercontaining 10 mM of Na₂HPO₄, 0.3% of bromophenol blue et 16% Ficoll areadded to samples which are subjected to electrophoresis in agarose gelsat 1.2% at 1 V/cm for 20 hours in a buffer containing 36 mM of Tris-HClat pH 7.8, 30 mM of Na₂HPO₄, 1 mM of EDTA and 2 μg/ml of chloroquine.The gels are stained with 2 μg/ml of ethidium bromide, photographedunder UV light at 312 nm with a camera and the fluorescent intensity ismeasured with a bioProfil camera (Vilber Lourmat, Lyon, France) with aview to determining the percentage of relaxed DNA. Each experiment iscarried out at least three times in duplicate.

In each experiment, the supercoiled plasmid DNA is incubated alone orwith topoisomerase 1. The reaction is completed within 15 minutes. Foreach compound to be tested or control, the supercoiled plasmid DNA isincubated in the presence of 500 μM of compound to be tested with enzymeor without enzyme plus the compound to be tested, at concentrations of10 μM, 100 μM, 200 μM and 500 μM. As indicated in Table I, Examples 2 to4, 9 to 11 and 76 to 79 inhibit the relaxation activity encouraged bytopoisomerase 1 in a dose-dependent manner.

TABLE I PERCENTAGE OF RELAXED DNA CONCENTATION (μM) EXAMPLE 10 100 200500 Example 2 97.9 78.3 73.2 51.1 Example 3 79.9 59.9 55.0 45.7 Example4 99.1 82.2 67.6 32.9 Example 9 77.1 33.9 29.7 20.4 Example 10 96.9 45.426.2 8.7 Example 11 65.0 50.3 39.8 31.0 Example 76 79.7 33.5 23.2 —Example 77 86.2 35.1 32.1 — Example 78 56.2 28.0 24.2 — Example 79 55.638.9 30.0 —

2. Test on Cell Proliferation

a. Eight tumoral cell lines are used in this study: L1210 (mouselymphocytic leukemia), HCT15 and LOVO (cell lines of human colonadenocarcinoma), A549 (human lung carcinoma), A172, U373 et U87 (humanglioblastoma). All these lines are obtained from the American TypeCulture Collection (ATCC), Rockville, Md. The L1210 cell cultures insuspension are cultured in Dulbecco's modified Eagle's medium (DMEM)(BioWhitaker, Verviers, Belgium) together with 10% of foetal calf seruminactivated by heating, 2 mM of glutamine, 50 U/ml of penicillin and 50μg/ml of streptomycin.

The HT29 cells are cultured in mono-layer cultures in a McCoy 5a medium(Gibco, Paisley, United Kingdom) together with 10% of foetal calf seruminactivated by heat plus 2 mM of glutamine and 50 μg/ml of gentamycin.The other cells are cultured in an Earle's modified essential medium(EMEM; Gibco, Paisley, United Kingdom) together with 5% foetal calfserum inactivated by heat, 2 mM of glutamine, 50 U/ml of penicillin and50 μg/ml of streptomycin. All the cell lines are cultured at 37° C. in ahumidified atmosphere containing 95% air and 5% CO₂.

Inhibition of the tumor cell line proliferation is determined using anMTT test. 1500 L1210 cells in a culture medium (according to the needsof the cell medium) are seeded in a well of a micro-well plate (tissueculture level: 96 wells, flat bottom) 24 hours before treatment with thecompounds to be tested. For these dose-response studies, the cells areincubated with each of the compounds to be tested or their correspondingsolvent (controls) for 48 hours over a final concentration range of1.10⁻¹⁰ to 1.10⁻⁴ M. All the compounds are dissolved just before use indimethylsulphoxide (DMSO) at a concentration of 50 mM. Other dilutionsof the medicaments are carried out in the culture medium. The finalconcentration of DMSO never exceeds 0.2% (v/v). As controls, thesolutions of medicaments are replaced with the solvent which is dilutedsuccessively in the same way as the compounds to be tested.

After the incubation period, the labeling reagent MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; Thiazolblue, Sigma M 565, Sigma, St Louis, Mo.) is added at a finalconcentration of 0.3 mg/ml to each well. The cells are incubated for 4hours at 370° C. in a humidified atmosphere. This stage allows themitochondrial dehydrogenase of the living cells to convert the yellowtetrazolium salt MTT into crimson formazan crystals. The supernatantpart is eliminated and the formazan crystals formed are solubilized withDMSO. The resultant coloured solution is quantified by absorbance at 570nm by using a multi-cuvette scanning spectrophotometer. The dataconcerning the proliferation is expressed as a percentage of livingcells in the treated wells, divided by the living cells in the controls.Each point represents the average of three independent experiments, eachexperiment represents six determinations.

For the other cell lines (HCT15, LOVO. A549, A172, U373, U87), 1000 to2000 cells are seeded in the well of a micro-well plate 24 hours beforemedicinal treatment. They are incubated with each of the compounds to betested or their corresponding solvent (controls) for 72 hours over afinal concentration range of 1.10⁻¹⁰ to 1.10⁻⁶ M. The results areexpressed as percentages of the calculated proliferation by the opticaldensity (OD) of the cells treated with a medicament divided by the OD ofthe control cells (cells treated with DMSO). As represented in Table II,the compounds to be tested have inhibited the proliferation of cells ina dose-dependent manner.

TABLE II PERCENTAGE OF CELL PROLIFERATION Cell EXAMPLE line 0.1 1 10 1001 000 10 000 100 000 Example 3 L1210 87.22 68.92 42.64 26.85 10.83 2.112.20 HCT15 86.00 84.00 58.00 44.00 18.00 9.00 13.00 LOVO 108.00 86.0054.00 31.00 23.00 10.00 12.00 A549 132.00 111.00 75.00 39.00 35.00 10.0011.00 A172 89.00 101.00 68.00 37.00 27.00 10.00 7.00 U373 99.00 98.0040.00 24.00 17.00 13.00 9.00 U87 108.00 85.00 42.00 23.00 15.00 5.006.00 Example 4 L1210 92.14 97.14 91.08 86.28 46.79 27.80 8.09 HCT1591.00 92.00 86.00 78.00 54.00 20.00 7.00 LOVO 80.00 75.00 79.00 69.0038.00 21.00 5.00 A549 71.00 76.00 71.00 56.00 36.00 22.00 12.00 A17293.00 92.00 98.00 97.00 44.00 31.00 10.00 U373 86.00 85.00 89.00 63.0030.00 16.00 2.00 U87 98.00 101.00 98.00 74.00 11.00 6.00 2.00 Example 9L1210 74.04 62.05 44.72 34.01 20.20 4.34 1.58 HCT15 94.00 89.00 59.0035.00 15.00 8.00 3.00 LOVO 74.00 85.00 44.00 31.00 21.00 4.00 2.00 A54991.00 88.00 50.00 31.00 23.00 5.00 3.00 A172 97.00 89.00 44.00 36.0019.00 3.00 1.00 U373 89.00 69.00 24.00 18.00 8.00 3.00 1.00 U87 105.0072.00 14.00 7.00 4.00 2.00 6.00 Example 10 L1210 91.51 97.94 89.28 67.3231.51 19.78 3.65 HCT15 111.00 87.00 103.00 63.00 42.00 17.00 9.00 LOVO71.00 76.00 77.00 52.00 29.00 18.00 4.00 A549 71.00 76.00 71.00 56.0036.00 22.00 7.00 A172 93.00 92.00 91.00 60.00 39.00 15.00 3.00 U37396.00 104.00 87.00 35.00 20.00 10.00 2.00 U87 96.00 79.00 89.00 17.006.00 5.00 2.00 Example 11 L1210 91.99 81.37 23.16 16.83 5.59 1.45 1.04HCT15 71.00 63.00 45.00 23.00 12.00 9.00 9.00 LOVO 66.00 42.00 29.0021.00 8.00 3.00 3.00 A549 82.00 44.00 29.00 26.00 4.00 3.00 2.00 A17295.00 53.00 47.00 39.00 12.00 3.00 2.00 U373 50.00 30.00 25.00 8.00 2.001.00 2.00 U87 40.00 21.00 12.00 6.00 1.00 1.00 1.00

b. Nine tumoral cell lines are used in this study: PC3, DU145 (humanprostate cell lines), MCF7 and MCF7-ADR (mammary cell lines, the symbol“ADR” is used to indicate that the line has been renderedadriamycin-resistant), A427 (human lung adenocarcinoma), HT29 (humancolon adenocarcinoma cell line), T24s, T24r (human bladder cell line,the T24r's are resistant to adriamycin, amongst others). The PC3, DU145and A427 lines were obtained from the American Type Culture Collection(ATCC, Rockville, Md.). The MCF7 and MCF7-ADR cells were graciouslydonated by Dr Jacques Soudon (Pharmacell, Paris, France). The T24s andT24r cells were graciously donated by Dr Robert Kiss (Free University ofBrussels, Belgium). The HT29 cells were cultivated in single-layercultures in a 4.5 g/l DMEM medium (Gibco, Paisley, United Kingdom)completed with 10% heat-inactivated foetal calf serum plus 2 mMglutamine and 50 g/ml gentamycin (Gibco, Paisley, United Kingdom). Theother cells are cultivated in a Earle's modified essential medium DMEMat 4.5 g/l (Gibco, Paisley, United Kingdom) completed with 10%heat-inactivated foetal calf serum, 2 mM glutamine (Gibco, Paisley,United Kingdom), 50 U/ml penicillin and 50 g/ml streptomycin(BioWhitaker, Verviers, Belgium). All the cell lines are cultivated at37° C. in a humidified atmosphere containing 95% air and 5% CO₂.

Inhibition of the tumour cell line proliferation is determined using aWST1 colorimetry test. 500 to 4000 cells in a culture medium (accordingto the needs of the cell medium) are seeded in a well of a micro-wellplate (96 wells, flat bottom) 24 hours before treatment with thecompounds to be tested. For these concentration-response studies, thecells are incubated with each of the compounds to be tested or theircorresponding solvent (controls) for 72 hours over a final concentrationrange of 1×10−13 to 1×10−5 M. All the compounds are dissolved indimethylsulphoxide (DMSO) or in water for the water-soluble compounds.The following dilutions of the compounds of the present invention arecarried out in the culture medium such that the final concentration ofDMSO, when it is part of the vehicle's composition, is always 0.1%(v/v). As controls, the solutions of the compounds are replaced with thesolvent which is diluted successively in the same way as the compoundsto be tested.

After incubation, the labelling reagent WST1(4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2h-5-tetrazolio-1,3-benzene)(Boehringer Mannheim, Germany) is added at a final concentration of 9%to each well. The cells are incubated for 2 to 4 hours at 37° C. in ahumidified atmosphere. This stage allows the mitochondrial dehydrogenaseof the living cells to convert the orange tetrazolium salt WST1 intocrimson formazan crystals. The resultant coloured solution is quantifiedby a dual beam reading (450 and 690 nm) using a multi-cuvette scanningspectrophotometer.

The results are expressed in the form of a concentration table,expressed in mol/litre, including the 50% inhibitory concentration(IC₅₀). They are shown in Tables III A) and III B). Examples where thenumber is followed by an “s” correspond to the compound salts. Cpt, Adrand Tpt are the abbreviations respectively for camptothecin, adriamycinand topotecan.

TABLE III A) Examples PC3 DU145 A427 HT29 CPT 10-7 to 10-8 10-7 to 10-810-8 to 10-7 10-7 to 10-8 Adr 10-7 to 108  Tpt 10-6 to 107  10-7 to 10-810-7 to 10-8 10-7 to 10-8 3 10-7 to 10-8 10-8 to 10-9 10-9 to 10-8 10-7to 10-8 16 <10-13 10-10 to 10-9  10-13 to 10-12 10-8 to 10-9 17 10-8 to10-9 10-12 to 10-11 10-11 to 10-10 10-8 to 10-9 18 10-13 to 10-12  10-9to 10-10 10-11 to 10-10 10-8 to 10-9 19 10-8 to 10-9  10-9 to 10-1010-10 to 10-9  10-8 to 10-9 20 <10-13 10-10 to 10-11 10-13 to 10-11 10-8to 10-9 21 10-8 to 10-9 10-8 to 10-9 10-11 to 10-10 10-7 to 10-8 22 10-7to 10-8 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 23 <10-13 10-10 to 10-1110-12 to 10-13 10-8 to 10-9 24 10-10 to 10-11 10-8 to 10-9 10-9 to 10-810-7 to 10-8 25 10-9 to 10-8  10-9 to 10-10 10-10 to 10-9  10-8 to 10-926 10-8 to 10-9  10-9 to 10-10 10-10 to 10-9  10-10 to 10-11 28 10-8 to10-9 10-10 to 10-11 10-10 to 10-9  10-8 to 10-7 29 10-13 to 10-12  10-9to 10-10 10-11 to 10-10 10-8 to 10-9 34  10-9 to 10-10 10-8 to 10-9 10-9to 10-8 10-7 to 10-8 37 10-7 to 10-8 10-8 to 10-9 10-9 to 10-8 10-7 to10-8 38 10-7 to 10-8 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 39 10-7 to10-8 10-7 to 10-8 10-9 to 10-8 10-8 to 10-9 39s 10-7 to 10-8 10-8 to10-9 10-9 to 10-8 10-7 to 10-8 42 10-7 to 10-8 10-8 to 10-9 10-9 to 10-810-8 to 10-9 44s 10-8 to 10-7 10-8 to 10-7 10-7 to 10-8 49 10-7 to 10-810-8 to 10-9 10-11 to 10-10 10-8 to 10-9 50 10-8 to 10-7 10-10 to 10-1110-8 to 10-7 10-7 to 10-8 53 10-7 to 10-8 10-8 to 10-9 10-9 to 10-8 10-7to 10-8 54 10-7 to 10-8 10-8 to 10-9 10-8 to 10-7 10-7 to 10-8 57  10-9to 10-10 10-9 to 10-8 10-7 to 10-8 57s 10-7 to 10-8 10-8 to 10-7 10-8 to10-7 58 10-7 to 10-8  10-9 to 10-10 10-8 to 10-9 10-7 to 10-8 58s 10-7to 10-8  10-9 to 10-10 10-9 to 10-8 10-8 to 10-9 59 10-7 to 10-8 10-8 to10-9 10-8 to 10-7 10-7 to 10-8 59s 10-8 to 10-7 10-9 to 10-8 10-8 to10-9 60 10-7 to 10-8  10-9 to 10-10  10-9 to 10-10 10-8 to 10-9 63 10-7to 10-8 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 63s 10-8 to 10-7 10-8 to10-7 10-8 to 10-7 64 10-7 to 10-8 10-10 to 10-11 10-9 to 10-8 10-8 to10-9 65 10-8 to 10-7 10-8 to 10-7 10-7 to 10-8 67 10-8 to 10-9 10-9 to10-8 10-7 to 10-8 81 10-8 10-9 82 3.10-8   7.10-9

TABLE III B) Examples MCF7 MCF7-ADR T24S T24R Cpt 10-6 to 10-7 10-8 to10-9 Adr 10-5 to 10-6 >10-4 Tpt 10-5 to 10-6 10-5 to 10-6 3 10-6 to 10-710-7 to 10-8 12 10-6 to 10-7 10-7 to 10-8 16 10-7 to 10-8 10-8 to 10-917 10-7 to 10-8 10-13 to 10-12 18 10-7 to 10-8 10-8 to 10-9 19 10-7 to10-8  10-9 to 10-10 22 10-6 to 10-7 10-8 to 10-9 23 10-7 to 10-8  10-9to 10-10 25 10-6 to 10-7 10-8 to 10-9 26 10-6 to 10-7 10-8 to 10-9 2810-7 to 10-8 10-8 to 10-9 39s 10-6 to 10-7 10-8 to 10-9 10-7 to 10-8 4210-6 to 10-7 10-8 to 10-9 43 <10-13 10-7 to 10-8 44 10-7 to 10-8 10-7 to10-8 44s 10-8 to 10-9 10-8 to 10-9 45 10-8 to 10-9 10-7 to 10-8 45s10-13 to 10-12 10-7 to 10-8 49s 10-8 to 10-9 10-7 to 10-8 57 10-6 to10-7 57s 10-10 to 10-9  10-8 to 10-9 59 10-6 to 10-7 59s 10-10 to 10-9 10-8 to 10-9 61 10-7 to 10-8 10-6 to 10-7 63s  10-9 to 10-10 10-7 to10-8 65 10-8 to 10-9 10-7 to 10-8 67 10-6 to 10-7 71 10-6 to 10-7 10-7to 10-8 10-7 to 10-8

What is claimed is:
 1. A method of treating a cancer selected from thegroup consisting of leukemia, colon cancer, lung cancer, prostate cancerand breast cancer in warm-blooded animals comprising administering towarm-blooded animals in need thereof a unsubstituted or pharmaceuticallyacceptable substituted camptothecin with a 7-ring member β-hydroxylactone ring of the formula

wherein R₁ is selected from the group consisting of alkyl of 1 to 6carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms haloalkyl of 1to 6 carbon atoms, alkoxy alkyl of 2 to 12 carbon atoms andalkylthioalkyl of 2 to 12 carbon atoms, R_(p) is hydrogen or an easilycleavable group, R₁₈ and R₁₉ are individually selected from the groupconsisting of hydrogen, halogen, OH and alkyl and alkoxy of 1 to 6carbon atoms and its non-toxic, pharmaceutically acceptable salts. 2.The method of claim 1 wherein R₁ ethyl.
 3. The method of claim 1 whereinR₁₈ and R₁₉ are hydrogen.
 4. The method of claim 2 wherein R₁₈ and R₁₉are hydrogen.
 5. The method of claim 1 wherein R_(p) is hydrogen.
 6. Themethod of claim 2 wherein R_(p) is hydrogen.
 7. The method of claim 1wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;11-[(dimethylamino)methyl]-5ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[3,6dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-([benzyl(methyl)amino]methyl)-9chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[2-b]quinolin-5-yl2-aminoacetate;5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinolin-5-yl3-aminopropanoate;2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino1,2-b]quinoline-11,14-dione;2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;(+)-5ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;or a pharmaceutically acceptable salt of the latter.
 8. The method ofclaim 1 wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-315-dione;5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[2-b]quinoline-3,15-dione;9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(dimethylamino)methyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(diisobutylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-12-[(dimethylamino)methyl]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10methyl-12[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-1,14-dione;2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methylhexahydropyridine;or a pharmaceutically acceptable salt of the latter.
 9. The method ofclaim 1 wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-1H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;9chloro-5-ethyl-5-hydroxy-10methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[(diethylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;or a pharmaceutically acceptable salt of the latter.
 10. The method ofclaim 1 wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2b]-quinoline-3,15-dione;5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;(+)-5-ethyl-9,10difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;or a pharmaceutically acceptable salt of the latter.
 11. The method ofclaim 1 wherein the camptothecin is(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneor(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridiumchloride.